Heterotrimeric G Proteins in the Control of Parathyroid Hormone Actions

Home , GNA11, GNAS complex locus, Gs alpha subunit

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m bastepe and others G proteins in PTH actions 58: 4 R203–R224 Review

Heterotrimeric G proteins in the control of parathyroid hormone actions

Murat Bastepe1, Serap Turan2 and Qing He1 Correspondence should be addressed 1 Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, to M Bastepe Boston, Massachusetts, USA Email 2 Department of Pediatric Endocrinology, Marmara University School of Medicine, Istanbul, Turkey [email protected]. edu

Abstract

Parathyroid hormone (PTH) is a key regulator of skeletal physiology and calcium and Key Words phosphate homeostasis. It acts on bone and kidney to stimulate bone turnover, increase ff PTH the circulating levels of 1,25 dihydroxyvitamin D and calcium and inhibit the reabsorption ff G proteins of phosphate from the glomerular filtrate. Dysregulated PTH actions contribute to or ff GNAS are the cause of several endocrine disorders. This calciotropic hormone exerts its actions ff bone via binding to the PTH/PTH-related peptide receptor (PTH1R), which couples to multiple ff kidney

heterotrimeric G proteins, including Gs and Gq/11. Genetic mutations affecting the

activity or expression of the alpha-subunit of Gs, encoded by the GNAS complex locus, are responsible for several human diseases for which the clinical findings result, at least partly, from aberrant PTH signaling. Here, we review the bone and renal actions of PTH with respect to the different signaling pathways downstream of these G proteins, as well Journal of Molecular Journal of Molecular Endocrinology as the disorders caused by GNAS mutations. Endocrinology (2017) 58, R203–R224

Introduction

Parathyroid hormone (PTH) is an 84-amino acid peptide Other regulators of PTH synthesis/secretion include secreted from the chief cells of the parathyroid glands 1,25-dihydroxyvitamin D, serum phosphate levels (Habener et al. 1984, Potts 2005). PTH is synthesized and the phosphaturic hormone fibroblast growth as a pre–pro hormone consisting of 115 amino acids. factor-23 (FGF23) (Silver et al. 1985, Moallem et al. 1998, The pre-sequence (25 amino acids), which serves as the Ben-Dov et al. 2007, Krajisnik et al. 2007). signal peptide necessary for the peptide’s delivery across The actions of PTH are critical for the maintenance the membrane of the endoplasmic reticulum, and the of serum calcium and phosphate levels and contribute pro-sequence (6 amino acids), which is thought to be directly to bone turnover and remodeling. Consistent necessary for efficient transport and proper folding, are with these roles, PTH exerts its actions primarily in bone removed prior to the secretion of the remaining 84-amino and kidney. It increases both bone formation and bone acid sequence, which makes up the mature PTH hormone resorption via its actions on osteoblasts, but the net effect (Kemper et al. 1974, Wiren et al. 1989). PTH secretion depends on the nature of PTH exposure. Intermittent is regulated through the actions of various factors, PTH administration favors bone formation and, thus, including blood-ionized calcium, which acts directly via has an anabolic effect on bone. This effect is utilized in its own G protein-coupled receptor (Brown et al. 1993). the clinic for treating osteoporosis in postmenopausal

10.1530/JME-16-0221 Journal of Molecular Endocrinology skeletal lesionsthatresultfromincreasedboneresorption. action causeshypercalcemia, hypophosphatemiaand with elevatedserumphosphate,whereasexcessPTH results inhypocalcemiaandreduced1,25(OH) lead toseveralendocrinediseases.DiminishedPTHaction Impaired orexcessactionsofthiscalciotropichormone serum calcium and a reduction in serum phosphate levels. the overall outcome of PTH actions are an elevation in absorption ofcalciumintheintestine,andtherefore, in theproximaltubule. 1,25(OH) (1,25(OH) the activevitaminDmetabolite1,25dihydroxyvitamin in thedistaltubule,whereasitstimulatessynthesisof Potts 2005 parts ofthe nephron arePTHtargets ( Rhee osteoblasts andosteocytes( directly stimulatestheproductionofFGF23inmature Potts 2005 patients withhyperparathyroidism ( levels, ontheotherhand,enhanceboneresorption,asin women ( DOI: 10.1530/JME-16-0221 http://jme.endocrinology-journals.org Review t al et Neer 2 . 2011 D) andinhibitsthereabsorptionofphosphate ). PTHenhancesthereabsorptionofcalcium ). Additionally, ithasbeenshownthatPTH t al et b ). Inkidney, bothproximalanddistal . 2001 ). ContinuouslyelevatedPTH Lavi-Moshayoff m

bastepe © 2017SocietyforEndocrinology Habener Habener 2 D stimulatesthe andothers Printed inGreatBritain t al et et al et al 2 D levels . 2010 . 1984 . 1984 , , , phospholipases, potassiumandcalciumionchannels specific effectors,suchasadenylylcyclases,certain and becomesavailableforregulatingtheactivitiesof bound alpha-subunitdissociatesfromtheG Cabrera-Vera of theheterotrimericGprotein( PTH inducesaGDP–GTPexchangeonthealpha-subunit G protein-coupledreceptors,stimulationofPTH1Rby of 39residues(TIP39)( actions oftheneuropeptide tuberoinfundibular peptide is nowknownthatthelatterreceptorprimarilyfor receptor, termedPTH2R( and activateanother, closelyrelatedGprotein-coupled ( G PTH1R couplestomultipledifferentGproteins,including family BGprotein-coupledreceptors( peptide (PTHrP)receptor(PTH1R),whichbelongstothe regulates arangeofeffectorproteins,somewhichare intracellular second messengers. The G and src tyrosinekinase, whichinturngeneratevarious G proteinsinPTHactions Fig. 1 Published byBioscientifica Ltd. s andG PTH exertsitsactionsthroughthePTH/PTH-related ). Theaminoterminalportion of PTHcanalsobind q/11 ( Abou-Samra t al et . 2003 pathways activatedbyPTH. A summarydiagramofGprotein-mediated Figure 1 Usdin Downloaded fromBioscientifica.com at09/28/202101:35:51PM , et al Usdin Syrovatkina . 1991 et al et al . 1999 , Bringhurst Bourne . 1995 Jüppner 58 t al et : β 4 ). Aswithother γ complex also . 2016 t al et ); however, it et al β et al γ subunits . 1991 . 1991 ). GTP- R204 . 1993 via freeaccess ). ). ) , Review m bastepe and others G proteins in PTH actions 58:4 R205

identical to those regulated by G alpha-subunits, such as (Boguslawski et al. 2000) and matrix metalloproteinase adenylyl cyclases, phospholipase Cβ and certain potassium 13 (Selvamurugan et al. 1998). These typically depend and calcium ion channels. The duration of G protein- on the activation of AP1 (activator protein 1) family of mediated intracellular signaling is tightly controlled transcription factors c-fos and c-jun via phosphorylation through the intrinsic GTP hydrolase activity of the alpha- of cAMP response element-binding protein (CREB) subunit, which limits the half-life of the GTP-bound (Clohisy et al. 1992, Pearman et al. 1996, McCauley et al. form. The GDP-bound alpha-subunit readily reassociates 1997), although other transcription factors are also with the Gβγ subunits and thereby resumes an inactive involved. For example, a role for αNAC (nascent conformation (Bourne et al. 1991, Cabrera-Vera et al. polypeptide-associated complex α-subunit) upon PKA 2003, Syrovatkina et al. 2016). The G protein activation phosphorylation has been described recently, particularly cycle is key to the actions of PTH, as well as numerous with respect to PTH-induced osteocalcin expression and other hormones, neurotransmistters and autocrine/ the anabolic effect of PTH on bone (Pellicelli et al. 2014). paracrine factors throughout the body. In this article, we PTH-induced changes in gene expression also involve review the G protein-dependent signaling pathways that intermediate kinases and phosphorylation events. A mediate the different actions of PTH in bone and kidney. recent study using both in vitro and in vivo approaches has In humans, defects within the gene encoding the alpha- shown that p38 mitogen-activated protein kinase (MAPK) subunit of the stimulatory G protein (GNAS) are associated is an important mediator of PTH actions downstream of with various phenotypes that directly reflect altered PTH PKA and that ablation of this protein in osteoblasts (using actions. Thus, we also review the GNAS-related diseases, osteocalcin–Cre) markedly impairs the osteoanabolic particularly focusing on clinical features resulting from activity of PTH (Thouverey & Caverzasio 2016). abnormal PTH signaling. PTH signaling also cross-talks with the Wnt/β-catenin signaling to promote osteogenesis. Wnt/β-catenin signaling pathway is an important promoter of osteoblast G /cAMP/PKA-mediated actions of PTH s differentiation and bone formation (Day et al. 2005, in bone Hill et al. 2005, Rodda & McMahon 2006). PKA can It has been shown that intermittent PTH treatment phosphorylate and increase the stability of β-catenin enhances the activation frequency of bone multicellular (Guo et al. 2010a). PTH1R signaling has been shown to units and osteoblast surface, as well as increasing osteoblast result in binding of the receptor to the Wnt co-receptor numbers and activity (Shen et al. 1993, Boyce et al. low-density lipoprotein receptor-related protein 6 (LRP6), Journal of Molecular Endocrinology 1996, Lane et al. 1996, Manolagas 2000). Studies have phosphorylation of the latter and stabilization of β-catenin revealed various different mechanisms underlying the in osteoblasts (Wan et al. 2008). It has also been shown bone anabolic action of PTH. These include stimulation that PTH-induced cAMP/PKA signaling phosphorylates of osteoblast proliferation and differentiation, inhibition and, thereby inactivates glycogen synthase kinase 3 of osteoblast apoptosis and activation of quiescent lining beta (GSK3β), thus promoting Wnt/β-catenin signaling cells (Dobnig & Turner 1997, Jilka et al. 1999, 2009, Iida- (Suzuki et al. 2008). Furthermore, PTH acts on osteocytes Klein et al. 2002, Bellido et al. 2003, Lindsay et al. 2006, to suppress the expression of sclerostin, an inhibitor of Jilka 2007, Kim et al. 2012). canonical Wnt signaling (Li et al. 2005, Semenov et al.

Gs is a ubiquitously expressed heterotrimeric protein 2005). PTH action on sclerostin is primarily through mediating the actions of many endogenous ligands cAMP signaling (Keller & Kneissel 2005) and mediated

(Weinstein et al. 2001). Although several effectors of the Gs by myocyte enhancer factor-2 (MEF2) transcriptional alpha-subunit (Gαs) have been described, by far the most regulators (Leupin et al. 2007). Using the cAMP signaling extensively studied and, evidently, the most important Gαs pathway in osteoblasts, PTH also inhibits the expression effector is adenylyl cyclase, which catalyzes the synthesis of Dickkopf 1 (Dkk1) (Guo et al. 2010a), which is another of the ubiquitous second messenger cyclic AMP (cAMP). A Wnt pathway inhibitor (Li et al. 2006, Morvan et al. 2006). major target of intracellular cAMP is the cAMP-dependent PTH exposure also activates osteoclastogenesis through protein kinase (PKA), which phosphorylates a whole host an indirect effect on stromal cells and/or mature osteoblasts of critical proteins to initiate specific cellular events. by activation of the receptor activator of nuclear factor-κ PKA-dependent PTH action increases the B/RANK ligand (RANK/RANKL) system (Lacey et al. 1998, expression levels of several osteoblast-specific genes, Quinn et al. 1998, Yasuda et al. 1998, Lee & Lorenzo 1999, such as Runx2 (Franceschi & Xiao 2003), osteocalcin Ma et al. 2001, Ben-awadh et al. 2014). RANKL is expressed

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0221 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:35:51PM via free access Journal of Molecular Endocrinology G protein-coupledreceptor inosteoblaststhroughout constitutive activationofG bone properties( mass withimprovedbone architecture andmechanical mutant inmatureosteoblasts alsoleadtoincreasedbone reduced ( bone massisincreasedandsclerostinexpression is mutant inlateosteoblastsandosteocytes,trabecular in transgenicmiceexpressingaconstitutivelyactivePKA in theosteoblastlineage( constitutively activePTH1RdependsonG has recentlybeenshownthattheincreaseinbonemassby signaling pathways ( version ofPTH1RpredominantlyactivatesG O’Brien expressed inosteoblastsorosteocytes( increases intrabecularbonemassmicewhenspecifically chondrodysplasia ( identified inpatientswithJansenmetaphyseal 2011 cAMP pathway( receptor-related 1 protein (Nurr1) downstream of the G signaling andoccursviatheactivationofnuclear ( PTH directlyinducestranscriptionofFGF23inbonecells using mousemodelsandculturedcellsdemonstratedthat ( production ofFGF23,animportantphosphaturichormone Lorenzo 2002 on FGF23productionisdependentWnt/ 2005 production ( production of1,25(OH) to anindirectactioninthesameregardbyincreasing osteoblastic cells( signaling pathway, asshowninvariousstudiesusing by PTH also occurs primarily through the G Stimulation ofRANKLandinhibitionOPGexpression & Lorenzo1999 also inhibitsOPGexpressioninearlyosteoblasts( ligand secretedfromosteoblasts( expression ofosteoprotegerin(OPG),aRANKLdecoy (M-CSF) andRANKLwithsimultaneousdecreaseinthe by exposuretomacrophagecolony-stimulatingfactor 1998 cells ofthemonocyte/macrophagelineage( and bindstoitsreceptor, RANK,whichispresenton on thesurfaceofstromalcellsandosteoblasts/osteocytes, Lavi-Moshayoff Consortium DOI: 10.1530/JME-16-0221 http://jme.endocrinology-journals.org Review A constitutivelyactivemutantformofPTH1R, Another actionofPTHinboneistostimulatethe b ). CurrentevidenceindicatesthattheeffectofPTH , , Li Meir et al t al et Kao et al . 2008 Collins t al et t al et ). . 2000 . 2014 , et al Lavi-Moshayoff Fu Onyia , Rhee . 2000 Schipani . 2013 et al Tascau et al . 2010 Schipani a ). Osteoclastogenesisisstimulated , . 2005 Fan 2 t al et et al D, whichalsostimulatesFGF23 , . 2002 ). ExpressionofthesamePKA t al et , Shimada Sinha et al et al α Rhee . 2011 s signalingbyanengineereds . 2000 , et al Kolek , . 1995 . 2016 Kondo m t al et et al Yasuda . 2016 t al et

. 1995 bastepe a © 2017SocietyforEndocrinology t al et ). , et al . 2011 Huang ) resultsinprofound In vitro . 2010 . 2016 ). et al Calvi andothers ). Accordingly, it . 2005 et al ). Inaddition, . 2001 Printed inGreatBritain b α . 2002 t al et ), inaddition , thismutant , Yasuda ). Moreover, . 1998 s expressions et al s -dependent Rhee , Saito ). Studies β α -catenin . 2004 s/cAMP s/cAMP , . 2001 ). PTH Lee & t al et et al et al Lee α s/ ). , . . . osteoclastic boneresorption( primarily duetoadecreaseinRANKLexpressionand bone volumebuthadincreasedcorticalthickness, spongiosaandreducedtrabecular formation ofprimary fragment ofthecollagenI differentiated osteoblasts(usingCredrivenbythe2.3-kb and coworkershavereportedthatablationofG in differentstagesofosteoblastdifferentiation.Sakamoto various mousemodelsinwhichG constraints. pathway and is subject to developmental stage-specific the effectofPTHonbonemassutilizesG detected ( ofage,noskeletalphenotypeis is delayeduntil4 weeks occurs inbonemass( activation isdelayeduntilbirth,amuchmilderincrease bone volumeinmice( resultsinadramaticincreasetrabecular embryogenesis global G in die soonafterbirth,featuresthathavebeenobserved And these mice are born with subcutaneous edema and Additionally, osteogenic maturationisacceleratedin expression oftheWntinhibitors sclerostinandDkk1. Wnt signalingthatresultsat leastinpartfromincreased and oneoftheunderlying mechanismsisattenuated in osteoblastnumberisthe mostprominentpathology and intramembranousossification.Themarkeddecrease osteoporosis duetoimpairmentofbothendochondral cular spacing( trabecular thicknessandnumber, aswellincreasedtrabe spongiosa withdecreased trabecular boneintheprimary protein in early osteoblast lineage, also results in reduced promoter-driven Cre (G mice) ( PTH1R (DSELmutant)deficientincouplingtoG formation robustly in knockinmiceexpressing a mutant however, appearsunlikely, asPTHcouldstimulatebone actions viaotherGproteins.Arolefor bone formation, suggesting that PTH exerts these specific PTH isabletostimulateosteoblastdifferentiationand in the osteoblast lineage. However, despite G blunted the actions of intermittent PTH on trabecular bone are and corticalbonemass( osterix promoter)revealsmarkedlyreducedtrabecular (using adoxycycline-regulatedCredrivenbythe 2002 G proteinsinPTHactions Published byBioscientifica Ltd. The roleofG The constitutive deletion of G Postnatal removalofG , Chen Guo in vivo α s-knockout models s-knockout ( Hsiao et al et al inmicewhichG Wu . 2010 . 2005 et al s et al signalinghasbeenstudieddirectlyin . 2008 Hsiao b , Hsiao . 2011 , Germain-Lee Sinha Downloaded fromBioscientifica.com at09/28/202101:35:51PM α 1 promoter)resultedinreduced α Sinha ). Thesestudieshighlightthat et al s α et al OsxKO ). G s intheosteoblastlineage s Yu et al α . 2010 Sakamoto et al α ), which ablates this . 2008 t al et s isablatedconditionally s α s . 2016 s isablatedpostnatally s OsxKO α et al . 1998 s using the osterix s 58 . 2016 ), andifactivation ). However, ifG micehavesevere : 4 ). . 2005 t al et , q/11 α Skinner ). Moreover, s deficiency,s signaling, s ). signaling q/11 . 2005 R206 (D/D α et al s in s α via freeaccess ). s . Review m bastepe and others G proteins in PTH actions 58:4 R207

mesenchymal progenitors committed to the osteoblast that specifically activate the αG s pathway and the DSEL- lineage, resulting in the depletion of osteoblasts and knockin mice (Guo et al. 2010b, Nagai et al. 2011). PTH1R accumulation of osteocytes. However, the bone that is interacts with Na(+)/H(+) exchanger regulatory factors present in GαsOsxKO mice is mainly woven, suggesting that (NHERF) 1 and 2 (Mahon et al. 2002). This interaction

Gs signaling plays an important role in the formation of seems to play a critical role in determining G protein orderly lamellar bone (Wu et al. 2011). coupling, switching the G protein coupling preference of

Gαs was also knocked out in late osteoblasts and PTH1R toward Gq/11 from Gs. Further molecular studies osteocytes by using Dmp1-Cre (Fulzele et al. 2013). These have demonstrated that, although the interaction of

mice show severe osteopenia, with decreased trabecular PTH1R with NHERF1 enhances Gq/11 coupling without

and cortical bone and diminished bone mineral density. affecting Gi or Gs coupling, the interaction of PTH1R with Osteocyte density is elevated, but the lacunar–canalicular NHERF2 alters coupling to these G proteins in a manner

network was reduced and disorganized. Interestingly, favoring activation of Gq/11 and reduction of cAMP these mice show increased myelopoiesis due to altered generation, i.e. promoting Gi coupling and inhibiting

bone marrow microenvironment. Gs coupling (Wang et al. 2010). It has also been shown that NHERFs are critical in the membrane retention of PTH1R (Wang et al. 2007). Based on additional studies of

Gs/cAMP/PKA-mediated actions of PTH NHERFs in kidney, it is clear that NHERF1 is required for in kidney the membrane targeting of NPT2a and that its ablation in mice results in phosphate wasting (Shenolikar et al. Actions in the renal proximal tubule 2002). Phosphorylation of NHERF1, which occurs by

PTH shows its renal effects by acting on both the proximal both Gs and Gq/11-mediated pathways, dissociates Npt2a and the distal part of the nephron. PTH1R protein is from NHERF1, thus allowing Npt2a internalization and expressed primarily in the epithelial cells of the proximal lysosomal trafficking (Weinman et al. 2007, Wang et al. and distal tubules but not in the thin limbs of Henle, 2012). collecting ducts or glomeruli (Lupp et al. 2010). Our group has recently investigated the specific role PTH has an indirect calcemic effect at the renal of Gαs in RPT by studying knockout mice in which Gαs proximal tubule (RPT) by increasing the circulating is ablated conditionally using Cre recombinase driven

level of 1,25(OH)2D (Rasmussen et al. 1972, Larkins et al. by the promoter of type-2 sodium–glucose cotransporter Sglt2KO 1974). Although 1,25(OH)2D synthesis is upregulated, (Gαs mice) (Zhu et al. 2016). The Cre driven by this Journal of Molecular Endocrinology its metabolism by 24-hydroxylation is reduced by the promoter is active in S1 and S2, but not in S3, segments action of PTH (Trechsel et al. 1979). These PTH actions of RPT. GαsSglt2KO mice are normophosphatemic but

are mainly mediated by Gαs signaling, which induces show hypocalcemia with reduced serum 1,25(OH)2D and the expression of the gene encoding 25-hydroxyvitamin elevated serum PTH levels. In addition, PTH-induced D 1α hydroxylase (Cyp27b1) and destabilizes the elevation in urinary cAMP excretion is blunted, together transcript encoding vitamin D 24-hydroxylase (Cyp24a1) with a mildly blunted reduction of serum phosphate in (Rasmussen et al. 1972, Larkins et al. 1974, Horiuchi et al. response to PTH. However, renal Cyp27b1 mRNA levels 1977, Henry 1985, Shigematsu et al. 1986, Brenza et al. are normal at baseline and after PTH injection, renal 1998, Zierold et al. 2001). Cyp27b1 mRNA increases markedly in these mice. This PTH inhibits the reabsorption of phosphate from the finding suggests that Gαs-independent signaling pathways glomerular filtrate in RPT by decreasing the abundance of play a role, at least partly, in the induction of Cyp27b1 by sodium-phosphate co-transporters NPT2a and NPT2c on PTH. Consistent with this interpretation, PKC activation the apical membrane, thus enhancing renal phosphate has been suggested to mediate the action of PTH in this

excretion (Keusch et al. 1998, Pfister et al. 1998). Both Gs regard (Janulis et al. 1992, Ro et al. 1992). Reduced serum Sglt2KO and Gq/11 signaling have roles in PTH-mediated phosphate 1,25(OH)2D levels in Gαs mice could be explained reabsorption in RPT (Pfister et al. 1999, Traebert et al. by elevated renal Cyp24a1 expression. As PTH regulates 2000, Capuano et al. 2007, Segawa et al. 2007, the stability of Cyp24a1 mRNA via a cAMP-dependent Cunningham et al. 2009, Weinman et al. 2011). It has mechanism (Zierold et al. 2001), the elevation of Cyp24a1

been well documented that Gs signaling has a role in the expression likely reflects the PTH resistance. In addition, Sglt2KO acute effects of PTH, whereas Gq/11 signaling is required for Gαs mice show increased FGF23 expression in bone long-term PTH effects based on studies with PTH analogs and a mildly elevated serum FGF23 (Zhu et al. 2016),

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0221 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:35:51PM via free access Journal of Molecular Endocrinology 1981 Another transcript isalsoderivedfrom thepaternal splice ontoexons2–13ofG most tissues.MaternallyexpressedNESP55 andthepaternallyexpressedXL scale. (B)and(C)paternallymaternally expressed paternal allele(NESP55)orthematernal allele(XL paternal (pat) including therenalproximaltubuleandthyroid.Boxesconnecting linesrepresenttheexonsandintrons,respectively. Maternal(mat)and and inmosttissues,G within DMRs.Thenon-methylatedpromoterisactiveanddrivestheexpression inaparent-of-origin-specificmanner. G The Figure 2 increases TRPV5-mediatedcalciuminfluxbyenhancing 1999 connecting duct has beenpostulated( reabsorption intheconnectingtubuleandcortical phorbol ester-insensitive PKC isotype to stimulate calcium cAMP-independent PTHactionwiththeinvolvementofa PKA andPKCactivation( reabsorptive roleofPTHindistaltubulerequiresboth However, ithasalsobeenshownthatthecalcium- perfused nephron segments ( of calciumbyincreasingcAMPgenerationinisolated van deGraaf intestine ( TRPV6 expressionismorewide-spread,includingthe distal convolutedtubuleandconnectingtubule,whereas Groot 5 and6(TRPV5TRPV6)( cell through the transient receptor potential vanilloid Friedman & Gesek 1993 ( of Careabsorptioninthedistalpartnephron PTH triggerscAMPsignalingandisamajorregulator Actions intherenal distaltubule Zhu ablation ofthematernalG Cyp27b1 arepresentinmiceheterozygousforuniversal biochemistries andrenalexpressionlevelsofCyp24a1 ( which isapotentinducerofCyp24a1expression Shimada Shareghi &Stoner1978 DOI: 10.1530/JME-16-0221 http://jme.endocrinology-journals.org Review GNAS et al , ). ActivationofthecAMP–PKApathwaybyPTH et al Lau &Bourdeau1989 complexlocusanditsgeneproducts.(A)InadditiontothatdrivingG . 2016 et al Hoenderop . 2008 GNAS et al . 2004 ). productsareillustratedaboveandbelow thegenestructure,respectively. ‘+++’indicatesmethylatedDMRpromoters eitheronthe αs ). TRPV5isexclusivelyexpressedinthe . 2006 promoterisactiveonbothparentalalleles;however, thepaternalG ). Ofnote,similarchangesinserum αs t al et . NotethattheportionofNESP55transcript derivedfromexons2to13arewithinthe3 ). PTHshowsreabsorptiveactivity ). Calcium is reabsorbed into the Friedman , . 2001 Chabardes α s allele( s Friedman & Gesek 1995 Hoenderop , m ,

Shimizu bastepe et al Nijenhuis © 2017SocietyforEndocrinology t al et α . 1996 Liu s, A/Band Hoenderop andothers GNAS GNAS Printed inGreatBritain et al t al et t al et . 1980 t al et allele,butthistranscriptismadefrom theantisensestrand( ). Moreover, products,respectively. G . 2003 GNAS . 2011 . 1990 . 2003 , t al et -AS1 exon1).Arrowsindicatedirection oftranscription.Thefigureisnotdrawnto Imai , de de a ). ). , , , . α s andA/Boriginatefromthesensestrand andusedistinctfirstexonsthat splice ontoexons2–13. A/B transcriptsuseindividual,upstreamfirstexonsthat ( rise to several other coding and non-coding transcripts G gene encoding G Human disorders causedby mutations inthe seem tobeinvolvedinthedistaltubularactionsofPTH. Thus, both cAMP-dependentand-independentpathways to the C-terminus of TRPV5 ( involve, atleastpartly, inhibitionofcalmodulinbinding surface ( the openingofaconstantTRPV5channelatcell expression issilencedinasmallsetoftissues,including parental alleles,i.e.biallelic.Nevertheless,paternalG promoter isnotmethylatedandshowsactivityonboth promoter drivesthetranscription.Incontrast,G methylated regions(DMR),andtheunmethylated monoallelic transcripts are located within differentially exclusively fromthepaternalallele.Thepromotersofthese maternal allele, XL Although NESP55isexpressedexclusivelyfromthe transcriptional profile, exon ofNESP55.Inadditiontothiscomplexityinits upstream ofthepromoterforXL transcript ( NESP55 (Neuroendocrine secretory protein-55),XL NESP55 (Neuroendocrinesecretory 2000 1999 Swaroop G proteinsinPTHactions αs i. 2 Fig. Published byBioscientifica Ltd. α expression,thelocuscontainsfourdistinctpromotersthatarelocated s is encoded s by the αs b , transcripts,whichuseexons1–13,are biallelicallyexpressedin , Hayward &Bonthron2000 Wroe ) ( de Groot et al αs Kozasa alleleissilenced,atleastpartially, inseveraltissues GNAS et al . 1991 . 2000 t al et et al -AS1), which originates immediately α , s, A/B and Hayward α . 2009 ). Exons 1–13 encode G GNAS s . 1988 GNAS Downloaded fromBioscientifica.com at09/28/202101:35:51PM GNAS ). ThisPTHeffectappearsto complex locus, which gives ′ -untranslated region. alsoproducesanantisense et al GNAS is an imprinted locus. αs , promoterisnon-methylated, GNAS , de Groot Ishikawa Li α –AS1 transcript). . 1998 s andspansthefirst et al 58 -AS1 are expressed : . 2000 4 a t al et , t al et b , Peters α b s, whereas s, , . 2011 Liu . 1990 R208 α et al s and et al α α via freeaccess ). ). s s . . , Review m bastepe and others G proteins in PTH actions 58:4 R209

renal proximal tubule, thyroid, pituitary and certain indicating a major role for enhanced PTH actions in parts of the brain (Yu et al. 1998, Hayward et al. 2001, the pathogenesis of fibrous dysplasia. Increased bone Germain-Lee et al. 2002, Mantovani et al. 2002, Liu et al. resorption with enhanced osteoclastogenesis is another 2003, Chen et al. 2009). This tissue-specific monoallelic feature of FD, which is mediated by excess production of expression of Gαs underlies the imprinted mode of IL-6 (Yamamoto et al. 1996) and RANKL (Piersanti et al. inheritance observed for some of the phenotypes resulting 2010). The osteomalacia is related, at least partly, to excess from GNAS mutations (see below). production of FGF23, which leads to hypophosphatemia (Riminucci et al. 2003, Kobayashi et al. 2006). As mentioned previously, PTH was shown to stimulate FGF23 production McCune–Albright syndrome and fibrous dysplasia via Gαs signaling, and thus, the enhanced FGF23 of bone production is plausibly driven by the increased cAMP Residues Arg201 and Gln227 of Gαs are crucial for the accumulation in the cells. Nevertheless, Gαs signaling intrinsic GTPase activity, and thus, mutations at these sites has also been shown to contribute to the processing of result in a constitutively active Gαs mutant (Landis et al. FGF23 into its inactive fragments (Bhattacharyya et al. 1989). By stimulating adenylyl cyclase, constitutively 2012). Moreover, it is conceivable that the excess FGF23 active Gαs causes overproduction of cAMP in a ligand- production is secondary to the aberrant differentiation of independent manner, promoting cellular responses that the stromal cells. are normally mediated by cAMP signaling. Somatic Gαs FD/MAS is a genetic but a non-inherited disease, mutations of this nature are found in various endocrine as no germline inheritance of the Gαs mutation has and non-endocrine tumors, such as growth hormone- thus far been reported. It is therefore postulated that secreting adenomas (Landis et al. 1989) (Table 1). The same activating Gαs mutations are incompatible with life Gαs mutant, most frequently with a substitution at residue and lead to embryonic lethality, unless the mutation- 201 (95% of reported cases), is the cause of McCune– bearing and wild-type cells form a mosaic (Happle 1986). Albright syndrome (MAS) or isolated fibrous dysplasia of Recently, however, a transgenic mouse model expressing bone (FD) (Weinstein et al. 1991, Schwindinger et al. 1992, a constitutively active Gαs mutant has been described, Alman et al. 1996). MAS is characterized by the presence in which the transgene was transmitted along multiple of FD together with hyperpigmented skin lesions (café-au generations (Saggio et al. 2014), casting doubts about this lait spots) and hyperactive endocrine organs including hypothesis. Nevertheless, the development of FD lesions pituitary, thyroid and adrenal (Boyce & Collins 1993). in this model occurs much later than expected based on

Journal of Molecular Endocrinology GNAS mutations in FD/MAS are post-zygotically acquired, the findings in humans, suggesting that there might be and therefore, the patients are mosaic (Weinstein et al. significant differences at the molecular level between this 1991, Lumbroso et al. 2004). The skin, bone and endocrine particular mouse model and human FD. systems are the most frequently affected tissues in MAS, and this finding indicates that a mutation occurs early in Albright’s hereditary osteodystrophy and embryogenesis, before the separation of the three germ pseudohypoparathyroidism layers. The phenotype of patients with FD/MAS depends on the extent of tissues containing the GNAS mutation Heterozygous inactivating mutations in Gαs-coding

and the role of Gs signaling in those tissues (Dumitrescu GNAS exons cause Albright’s hereditary osteodystrophy & Collins 2008). (AHO), characterized by obesity with round face, short FD is an unregularly growing excess bone, causing a stature, brachydactyly, subcutaneous ossification and localized increase in bone mass. Bone pathology shows cognitive impairment (Albright et al. 1942, Patten et al. spicules of woven bone and undermineralized bone 1990, Weinstein et al. 1990) (Table 1). These patients also matrix embedded in a mass of connective tissue made of show resistance to PTH in the RPT with blunted urinary abnormal, poorly differentiated stromal cells (Marie et al. cAMP and phosphate excretion in response to exogenous 1997, Riminucci et al. 1997, 1999). This fibrosis is PTH, termed pseudohypoparathyroidism (PHP) type-I reminiscent of that seen in patients with severe primary (Albright et al. 1942, Chase et al. 1969). Hypocalcemia or secondary hyperparathyroidism (Kumbasar et al. and hyperphosphatemia with elevated PTH levels are 2004). Likewise, mice expressing a constitutively active the typical biochemical features of PHP type-I. Only PTH1R mutant also display significant accumulation of mutations on the maternal allele cause PTH resistance, fibroblastoid cells in the bone marrow (Calvi et al. 2001), owing to the silencing of the paternal Gαs allele in RPT

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a . 1998 b andothers Mild hormoneresistancehasbeendetectedinsomePPHPcases. Printed inGreatBritain Parental origin Maternal Paternal Paternal Maternal Maternal Somatic Somatic Mosaic Post-zygotic ). GNAS

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stromal tumor hyperplasia, sexcord macronodular adrenal secreting hormone-secreting, ACTH gonadotrophins) (e.g., GHRH, gonadotrophins) (e.g., GHRH, GNAS c b ossifications inskinandsubcutaneous tissues,butthese POH initiallydisplayectopic, extra-skeletalheterotopic progressive osseousheteroplasia (POH).Patientswith thesamemutations,termed in somepatientscarrying mutations, moreextensiveossificationhasbeendetected finding inpatientswithheterozygousinactivating G Mouallem patients with PHP-Ia rather than PPHP ( impairment, which appear to develop predominantly in the mutation,withexceptionofobesityandcognitive AHO featuresdevelop regardless oftheparental origin of upon paternalinheritance( whereas thesamemutationcausesPPHP(i.e. AHO alone) G proteinsinPTHactions Published byBioscientifica Ltd. . Although subcutaneousossificationisnotarare d Some patientscanhaveAHOfeatures. et al f In familialcases, . 2008 ). features clinical Additional AHO No No Café au-lait POFD No No AHO AHO Downloaded fromBioscientifica.com at09/28/202101:35:51PM GNAS spot d c

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subsequently invade deep connective tissues and exon 13 – encoding the C-terminal portion – have been skeletal muscle (Kaplan & Shore 2000). It has been identified, and the mutant protein was shown to affect shown that POH has a mosaic distribution through the receptor coupling but not the basal activity (Linglart et al. dermomyotomes, which is similar to the skin lesions 2002, 2006, Thiele et al. 2011). Thus, when Gαs activity

observed in MAS (Cairns et al. 2013). Based on this is assessed in patients using direct stimulators of Gs finding, it has been suggested that a somatic mutation rather than receptor agonists, those Gαs mutants appear in a progenitor cell of somitic origin causes loss of functional, suggesting that the diagnosis of PHP-Ic, at heterozygosity at the GNAS locus, thus leading to POH least in some cases, may reflect the limitation of the Gαs (Cairns et al. 2013). Investigation of multiple kindreds activity assay employed. with POH revealed that this disease is predominantly Another subtype is PHP-Ib (Table 1), which refers to inherited through paternal Gαs mutations, suggesting patients who present with PTH and, in some cases, mild that the disruption of one of paternally expressed GNAS TSH resistance in the absence of AHO features (Peterman products contributes to the pathogenesis (Shore et al. & Garvey 1949, Reynolds et al. 1952). Several studies, 2002). Recently, it was shown that activated hedgehog however, have recently indicated that PHP-Ib patients can signaling is a major player in heterotopic ossification also have certain AHO features (de Nanclares et al. 2007, caused by inactivating GNAS mutations, suggesting that Mariot et al. 2008, Unluturk et al. 2008, Mantovani et al. inhibition of this pathway could be a future drug target 2010). PHP-Ib is caused by methylation changes within for POH (Regard et al. 2013). the GNAS locus (Liu et al. 2000a). The patients show Most AHO features could be attributed to diminished loss of methylation at exon A/B with biallelic expression signaling downstream of PTH1R, which binds not only of the A/B transcript, whereas some cases display PTH but also PTH-related peptide (PTHrP), a paracrine methylation defects at additional GNAS DMRs (Liu et al. factor that plays a crucial role in endochondral bone 2000a, Bastepe et al. 2001b). Like in PHP-Ia, hormone development (Karaplis et al. 1994). Brachydactyly (type resistance in PHP-Ib is inherited maternally (Jüppner et al. E) and short stature are due to impaired PTHrP actions in 1998). The loss of A/B methylation and/or derepressed endochondral bone formation, similar to that observed A/B promoter activity on the maternal allele leads to in patients with mutations in either HDAC4 or PTHLH silencing of Gαs in cis, and this silencing takes place in (gene-encoding PTHrP) (Klopocki et al. 2010, Maass et al. tissues where Gαs expression normally occurs, exclusively 2010, Williams et al. 2010). Of note, these AHO features or predominantly, from the maternal allele, such as the are also found, in a more severe manner, in patients renal proximal tubule and thyroid. Thus, Gαs expression Journal of Molecular Endocrinology carrying mutations in PRKAR1A or PDE4D, which encode in those tissues is suppressed on both GNAS alleles. the type 1A PKA regulatory subunit or the type 4D cAMP Genetic changes that lead to these GNAS methylation phosphodiesterase, respectively (Linglart et al. 2011, abnormalities have been discovered in most familial cases Lee et al. 2012, Michot et al. 2012), further highlighting with PHP-Ib and include various microdeletions either at

the importance of reduced Gs signaling in the the neighboring STX16 locus, located ~200 kb centromeric pathogenesis. On the other hand, evidence suggests that to GNAS, or at the NESP55 DMR (Bastepe et al. 2003, 2005, ectopic ossifications, at least those observed in patients Linglart et al. 2005, Chillambhi et al. 2010, Richard et al. with POH, may result from deficient Gαs signaling 2012, Elli et al. 2014, Rezwan et al. 2015, Takatani et al. downstream of other receptors. Although ablation of Gαs 2016). A recent study has also revealed a large genomic in the mouse limb bud mesenchyme – through the use inversion that disrupts the GNAS locus as a cause of of Prx1–Cre – results in a severe phenotype resembling PHP-Ib (Grigelioniene et al. 2017). Sporadic PHP-Ib cases POH (Regard et al. 2013), ablation of PTH1R using the display broad methylation abnormalities within GNAS, same approach does not lead to ectopic ossification including loss of A/B methylation, and in some of these (Fan et al. 2016). cases, the underlying cause is paternal uniparental disomy Two additional subtypes of PHP type-I have been involving chromosome 20 (Bastepe et al. 2001a). described. PHP-Ic is phenotypically identical to PHP-Ia (Table 1). The genetic defect may be downstream of Gq/11/PLC/PKC-mediated PTH actions in bone Gαs in these cases, as Gαs activity appears normal in easily accessible cells from patients with PHP-Ic, unlike In addition to Gs, the PTH1R couples to Gq/11-dependent those from patients with PHP-Ia (Farfel et al. 1981). In activation of phospholipase C (PLC) (Abou-Samra et al. several PHP-Ic cases, however, Gαs mutations within 1991, 1992, Bringhurst et al. 1993). Upon activation,

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0221 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:35:51PM via free access Journal of Molecular Endocrinology mice, includingadiminished peritrabecularstromalcell D/D miceshowsignificant differencesfromwild-type 2004 G of PTHrP, demonstratingthatthe G ( and abnormalitiesinendochondralboneformation delayed hypertrophicdifferentiationofchondrocytes signaling ( G a mutatedPTH1R(DSELmutant)thatcanstimulate knockin mouse model has been generated, expressing the roleofG action of PTH in bone is less well characterized than in additiontoPKA( gene expressionappearstoinvolvePKC-deltaactivation, of insulin-like growth factor-binding protein-5 (IGFBP-5) ( the effects of PTH stimulation on MMP13 expression altering thecAMPresponsetoPTH,anditalsoenhances 01 significantlyincreasesPTH1RcouplingtoPLCwithout ( roleinosteoblastdifferentiation alpha playsaninhibitory 2001 osteoblast proliferation( ( also activatesPKC-deltaviaaPLC-independentpathway ( (1–34), as well as PTH (3–34), PTHrP and PTH (1–31) membrane translocationofPKC-alphainducedbyPTH forthe study showedthatphospholipaseDisnecessary different PKCisozymeshavealsobeensuggested.One PLC-independent mechanismsfortheactivationof IP3 generation( osteoblastic cellsfrommousecalvaria,PTHalsoinduces indicating activation of phospholipaseC.Inprimary 1991 the activationofG UMR106 andROScells),PTHtreatmentresultsin and PKAactions( of PTH1R is negatively regulated by the phosphorylation protein kinaseC(PKC)isozymes.PTHsignalingtoPLC turn, increaseintracellularCa Vera membrane phospholipids( (DAG) throughtheactionofphospholipaseCon inositol 1,4,5-trisphosphate(IP3)anddiacylglycerol G Guo Cheung Nakura Yang Radeff DOI: 10.1530/JME-16-0221 http://jme.endocrinology-journals.org s q/11 αs Review signalingingrowthplatechondrocytes ( /cAMP/PKA signalingbutnotG The In osteosarcoma-derived osteoblast-likecells(e.g. leadstothegenerationofsecondmessengers ). When fed a low-calcium diet or infused with PTH, , ). On the other hand, it has also been shown that PKC- et al et al t al et 1992 et al t al et et al in vivo . 2003 . 2002 Iida-Klein . 2006 ). ThisisevidencedbyaccumulationofIP3, . 2011 . 2004 . 2005 s inthesameregard.Asdiscussedabove,a , roleofG Farndale ). These findings reflect impaired actions Syrovatkina ). Via activationofPKC,PTHincreases Tawfeek &Abou-Samra2008 ). Overexpression of G ). AnotherstudyindicatedthatPTH ). Inaddition,PTH-inducedregulation Erclik &Mitchell2002 et al q/11 Miao et al signaling( . 1997 q/11 Bourne et al signalinginmediatingthe . 1988 et al 2+ andactivatedownstream ). Themice(D/D)exhibit . 2016 m

. 2001 bastepe © 2017SocietyforEndocrinology ). Ontheotherhand, q/11 t al et Abou-Samra signalingopposes ). IP3andDAG,in andothers , . 1991 α Swarthout Printed inGreatBritain 11 in UMR106- ). Bastepe q/11 ). , /PLC/PKC Cabrera- t al et et al et al . . . response toPTHtreatment( trabecular or cortical bone in G in remained unchanged,andnochangeswereobserved found similareffects.Boneformationorboneresorption specifically overexpressnativeG ( do not respond to PTH treatment regarding bone volume exhibit osteopenia and decreased bone formation, and (using the2.3-kbfragmentofCol1a1promoter) overexpression ofaconstitutivelyactiveG responses toPTH. for bonemodelingandremodeling,aswellnormal indicate thatthePLC–PKCsignalingpathwayisessential differentiation ability( formation and proliferation, but normal osteogenic isolated fromD/Dmicealsoshowattenuatedcolony 2010 with phorbol esters, a pharmacological activator of Hruska 1990 C/PKC inregulatingrenal actionsofPTH( membranes have demonstrated a role of phospholipase cells, amodelofRPT, andproximaltubule basolateral 1993 signaling inassays using LLCPK-1cells( phosphate transporthasbeenshowntorelyonPLC generation ( mechanism dampensthelevelofPTH-inducedIP3 ofPLC-beta3by aPKA-mediated and phosphorylation markedly diminishestheeffectofPTHonPLCsignaling, and/or G LLCPK-1 porcine renal tubularcells, reduction of G of PLC( renal cortical tubular cells, thus demonstrating activation GTP analog,resultsintheaccumulationofIP3canine been shownthatadditionofPTH,aswellastable via itseffectsontheapicalNPT2acotransporter. Ithas the PTH-inducedinhibitionofphosphatereabsorption The G in kidney G and PTHosteoanabolicaction. inhibits bonedevelopment,osteogenicdifferentiation ( bone volumeandturnoverthanthewild-typemice of G the otherhand,micewithosteoblast-specificablation response andreducednewboneformation( G proteinsinPTHactions Ogata Ogata Published byBioscientifica Ltd. q/11 Transgenic micewithosteoblast-specific α b ). Moreover, experimentsusingopossumkidney(OK) /PLC/PKC-mediated PTHactions q/G ). Bone marrow cells and primary osteoblasts ). Bonemarrowcellsandprimary q/11 t al et et al signalingpathwayhasalsobeenimplicatedin α α Coleman &Bilezikian1990 11 levelsbytheuseofsmall-interferingRNA 11 exhibit,upondailyPTHinjections,higher . 2011 . 2007 Tawfeek &Abou-Samra2008 , Azarani ). TheseresultssuggestG ). Astudyusingtransgenicmicethat t al et Guo Downloaded fromBioscientifica.com at09/28/202101:35:51PM . 1995 et al Dela Cruz . 2010 α ). Moreover, treatment 11 transgenic mice in α 11 inosteoblasts 58 b ). Intransfected t al et : ). Thesefindings 4 ). PTH-regulated Bringhurst α q/G . 2016 α Guo Dunlay & q mutant α 11 signal R212 ). On t al et et al α via freeaccess q . . Review m bastepe and others G proteins in PTH actions 58:4 R213

PKCs, in OK cells mimics the inhibitory effect of PTH nearly all exons are shared between XLαs and Gαs, and significantly suppresses the expression and activity XLαs is identical to Gαs over almost the entire amino of NPT2a (Cole et al. 1987, Malmström et al. 1988, acid sequence but contains a unique and much larger Quamme et al. 1989a,b, Pfister et al. 1999). Similar results N terminus. As indicated previously, Gαs is expressed were observed ex vivo using isolated intact proximal biallelically in most tissues, whereas the maternal allele tubules of mice treated with 1,2-dioctanoylglycerol of XLαs is silenced, i.e. XLαs is expressed exclusively from (DOG), an activator of PKC pathway, and based on further the paternal GNAS allele. XLαs is abundantly expressed in analyses, it has been suggested that the PLC/PKC pathway neuroendocrine tissues, particularly pituitary, and brain, predominantly regulates the actions of PTH in the apical its expression is also detectable in pancreas, kidney, bone membrane (Traebert et al. 2000). Impaired PTH-induced and muscle (Kehlenbach et al. 1994, Pasolli et al. 2000, PLC stimulation in Nherf1-deficient mice, which fail Pasolli & Huttner 2001, Liu et al. 2011a, Pignolo et al. to couple apical PTH1Rs to PLC/PKC, also suggests that 2011, Krechowec et al. 2012). Because Gαs and XLαs apical PTH1R preferably couples to the PLC/PKC pathway share the amino acid sequences encoded by exons 2–13, (Capuano et al. 2007). In addition, studies with the D/D disease-causing GNAS mutations that are located in these mice (see above) have provided further support for an exons affect both Gαs and XLαs when they are on the important role for the PLC/PKC pathway in PTH-induced paternal allele. Thus, all mutations that are responsible inhibition of renal phosphate reabsorption in vivo. for PPHP, except for those located in exon 1, disrupt Although wild-type mice show dramatically decreased XLαs activity. Moreover, when present on the paternal serum phosphate levels in response to continuous GNAS copy, all mutations found in patients with FD/MAS infusion of PTH (1–34), the D/D mice display only a and multiple tumors, which are located in exons 8 or

transient response (Guo et al. 2013). Thus, the Gq/11 9, affect XLαs activity. XLαs inactivation is specifically pathway is essential for the normal renal actions of PTH implicated in progressive osseous heteroplasia, which on phosphate reabsorption. is predominantly, but not always, inherited paternally,

It is important to note that Gq/11 proteins also play and in severe intrauterine growth retardation observed a crucial role in regulating PTH generation as the action in PPHP, whereas XLαs hyperactivity in the formation of the calcium-sensing receptor is primarily mediated of thyroid and ovarian tumors in patients with MAS by these G proteins (Hofer & Brown 2003, Ward 2004). (Shore et al. 2002, Mariot et al. 2011, Richard et al. 2013). Parathyroid gland-specific αG q/Gα11 double-knockout In addition, increased XLαs activity has been implicated in mice exhibit parathyroid hyperplasia, markedly increased the development of 20q-amplified breast tumors (Garcia-

Journal of Molecular Endocrinology serum calcium and PTH, severe delay in bone formation Murillas et al. 2013). and resorption (Wettschureck et al. 2007). Similar findings Studies using transfected cells overexpressing XLαs are also present in transgenic mice in which the PTH suggest that it can mimic the action of Gαs with respect promoter drives expression of the C-terminal peptide of to PTH-induced cAMP generation (Bastepe et al. 2002, Gαq, which specifically inhibits the latter Pi( et al. 2008). Linglart et al. 2006). XLαs, like Gαs, is localized to the In humans, mutations in GNA11, which encodes Gα11, plasma membrane at the basal state (Pasolli et al. 2000, also correlate with dysregulated PTH levels. Inactivating Linglart et al. 2006). However, activated XLαs and Gαs mutations in GNA11 have been identified as a cause of traffic differently in XLαs- or Gαs-transfected cells. XLαs familial hypocalciuric hypercalcemia type 2, whereas remains at the plasma membrane after PTH stimulation, gain-of-function mutations in this gene were shown to be whereas Gαs redistributes to the cytosol (Liu et al. 2011b). responsible for autosomal dominant hypocalcemia type 2 This property of XLαs is consistent with higher basal (Mannstadt et al. 2013, Nesbit et al. 2013, Li et al. 2014). activity of GTPase-deficient XLαs mutants in transfected cells and may explain the finding that XLαs overexpression significantly prolongs the cAMP response induced by XL s-mediated actions of PTH α a typically short-acting PTH analog (M-PTH (1–14)) XLαs is a large variant of Gαs derived from the imprinted (Liu et al. 2011b). In addition, when XLαs is expressed GNAS complex locus (Kehlenbach et al. 1994). XLαs ectopically in the renal proximal tubules in transgenic uses an alternative upstream promoter and a distinct (rptXLαs) mice, overexpressed XLαs enhances the cellular first exon, but shares the same exons 2–13 with Gαs responses downstream of Gαs signaling (Liu et al. 2011a). (Hayward et al. 1998a, Peters et al. 1999) (Fig. 2). Because And transgenic overexpression of XLαs in renal proximal

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0221 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:35:51PM via free access Journal of Molecular Endocrinology including Mmp8,Gadd45a and Foxa2( PTH inaG cells identifiedasmallset of genesthatareregulatedby PTH, experimentsusingantagonist minigenesinUMR106 to beclarifiedwithrespect to thephysiologicalactionsof overall significanceofPTH1RcouplingtoG of G showed thatPTH-inducedPLDactivation was downstream A subsequent study by the same group of investigators and thebioactivelipidphosphatidicacid( that hydrolyzesphosphatidylcholinetogeneratecholine manner, the activityofphospholipaseD(PLD),anenzyme demonstrated thatPTHstimulates,inaRhoA-dependent By usingosteoblastic UMR106 cells, it has been Other Gproteins intheactionsofPTH of PTHduringearlypostnataldevelopment. PKC pathway XL activation ( in vivo of XL in XLKOmiceatpostnatalday2andthatoverexpression the abundancesofPKC found thatbasalandPTH-stimulatedIP3signaling increased serumPTH( hyperphosphatemia and hypocalcemia, together with found that at early postnatal age, XLKO mice exhibit 2005 in miceheterozygousforG from andare,bylarge,oppositeofthoseobserved Richard XLKO mice( in fattissuesthatarereminiscentofthephenotypes been implicatedtohavefeedingdifficultiesanddefects humans, lossoffunctionpaternal have beenknockedout( 2, inwhichthepaternalallelesofbothG in miceheterozygousfordeletedpaternalGnasexon 2004 defects inglucoseandenergymetabolism( hypermetabolism andreducedadiposity, andhave poor adaptationtofeeding,earlypostnatallethality, the actions of G (XLKO) micesuggestthatXL overexpressed, mice withablationofmaternalG tubules partiallyrescuesthePTHresistancephenotypeof DOI: 10.1530/JME-16-0221 http://jme.endocrinology-journals.org Review α Although XL s canpromoteG , ). Thesephenotypesaresimilartothoseobserved 12/13 α s in transfected cells or in renal proximal tubules stimulates IP3 generationand PKC isozymes Germain-Lee activation ( t al et He 12 -, butnotG Aldred . 2013 in vivo et al in vivo αs α . Mice in which XL . 2015 s displays a G t al et andisrequiredfortherenalactions ). Thesephenotypesdiffervastly q/11 t al et Singh He studiesusingXL δ signalingtostimulatethePLC/ ). Theseresultsdemonstratethat , PKC Yu . 2002 t al et s - orG . 2005 αs t al et et al α ablationalone( s hasactionsdistinctfrom α . 2015 andPKC , m αs . 1998 q/11 . 2005 Genevieve

). We haverecently bastepe © 2017SocietyforEndocrinology ( -dependent manner, Liu αs ). We additionally α Wang -like role when s is ablated show , andothers Singh et al GNAS 2000 ). Although the Printed inGreatBritain ζ arerepressed αs . 2011 t al et 12/13 α Plagge et al et al s-knockout allelehas Chen , andXL 2001 remains . 2011 . 2005 . 2003 a et al ). et al ). In α ). ). s , . . ( as OKcells,inadose-andtime-dependentmanner signaling pathway in several different cell lines, such the regulationofPTH1Ruponactivation. G and trafficking ( and PLD2havebeenfoundtoregulatePTH1Rendocytosis In addition,basedonstudiesusingculturedcells,PLD1 phosphorylation byPTHoccursinabiphasicmanner,phosphorylation cells andvariouspharmacologicinhibitors,thatERK1/2 & Defize1997 ERK1/2, wasindependentofrasactivation( of kinase signaling,asjudgedbythephosphorylation also indicatedthatthePTH-inducedactivationofMAP occurs viabothofthosesignalingpathways.Onestudy PLC/PKC pathways, concluding that the effect of PTH inhibitors todifferentiallyalterG 2000 By employingtheseligands, itwasthenshownthat receptor internalization( hand, PTH (1–31)activates the PTH1R without causing inducing cAMPorPLCsignaling pathways. Ontheother cells, PTH(7–34)inducesreceptor endocytosiswithout both activates and internalizes PTH1R in distal kidney 2007 factor receptor(EGFR)( (HB-EGF) andtransactivationoftheepidermalgrowth heparin-binding fragment of epidermalgrowth factor metalloprotease-mediated cleavageofmembrane-bound the G revealed thatPTHcanstimulateERK1/2signalingthrough in OK cells ( phosphorylation suggested intheactionofPTHasastimulatorERK1/2 An involvement of epidermalgrowth factor has been depends onG phasethat identification oftheERK1/2phosphorylation alleles of line in which exon 2 was ablated from both parental fibroblast The studyalsoutilizedamouseembryonic protein-independent manner( a latephasethatinvolvestheactionofbeta-arrestininG has anearlyphasethatreliesonG inthesecells the PTH-inducedERK1/2phosphorylation human PTH1RcDNAhassubsequentlydeterminedthat kidney 293(HEK293)cellstransientlytransfectedwiththe 2000 late phasedependentonproteinkinaseC( phosphatidylinositol-4,5-bisphosphate 3-kinase andthe with theearlierphasemediatedbytyrosinekinaseand G proteinsinPTHactions Verheijen &Defize 1997 Published byBioscientifica Ltd. 12/13 PTH hasbeenshowntostimulatetheMAPkinase ). These studies used various stimulators and ). In contrast, another study using human embryonic ). Incontrast,anotherstudyusinghumanembryonic ). Ithasbeenshownthat, although PTH(1–34) i mediates certain specific actions ofPTH, as well as signalingpathway, whichleadstothestimulation of Gnas s /cAMP signaling( ( ). Ithasalsobeenshown,byusingOK Garrido Bastepe Ahmed et al Downloaded fromBioscientifica.com at09/28/202101:35:51PM t al et Sneddon , . 2009 . 2002 Cole 1999 Cole 1999 et al Gesty-Palmer Gesty-Palmer s andG s /cAMP/PKA andG ). It thusappears that t al et . 2003 ); thesecellsallowed 58 q/11 : ). Further studies 4 , , . 2003 Lederer Sneddon pathwaysand Lederer et al et al Verheijen , . 2006 2004 . 2006 t al et R214 et al et al q/11 via freeaccess ). ). ). / . . . Review m bastepe and others G proteins in PTH actions 58:4 R215

PTH1R activation, but not internalization, is required for within the imprinted GNAS1 locus. Human Molecular Genetics 10 stimulation of MAP kinase signaling in distal kidney cells 1231–1241. (doi:10.1093/hmg/10.12.1231) Bastepe M, Gunes Y, Perez-Villamil B, Hunzelman J, Weinstein LS & (Sneddon et al. 2007). Jüppner H 2002 Receptor-mediated adenylyl cyclase activation through XLalphas, the extra-large variant of the stimulatory G protein alpha-subunit. Molecular Endocrinology 16 1912–1919. (doi:10.1210/me.2002-0054) Declaration of interest Bastepe M, Fröhlich LF, Hendy GN, Indridason OS, Josse RG, The authors declare that there is no conflict of interest that could be Koshiyama H, Körkkö J, Nakamoto JM, Rosenbloom AL, perceived as prejudicing the impartiality of this review. Slyper AH, et al. 2003 Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. Journal of Clinical Investigation 112 1255–1263. Funding (doi:10.1172/JCI19159) The studies conducted by the corresponding author’s lab have been funded, Bastepe M, Weinstein LS, Ogata N, Kawaguchi H, Jüppner H, in part, by the National Institutes of Health (NIDDK, RO1 DK073911), the Kronenberg HM & Chung UI 2004 Stimulatory G protein directly March of Dimes, the Milton Fund and the Fibrous Dysplasia Foundation. regulates hypertrophic differentiation of growth plate cartilage in vivo. PNAS 101 14794–14799. (doi:10.1073/pnas.0405091101) Bastepe M, Fröhlich LF, Linglart A, Abu-zahra HS, Tojo K, Ward LM & Jüppner H 2005 Deletion of the NESP55 differentially methylated References region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type-Ib. Nature Genetics 37 25–37. 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