Lithium, Cyclic AMP Signaling, A-Kinase Anchoring Proteins, and Aquaporin-2

Editorial

Daniel G. Bichet Departments of Medicine and Physiology, and Groupe d’e´tude des proteínes membranaires, Universite´de Montreál, and Centre de recherche and Service de ne´phrologie, Hoˆpital du Sacre´-Coeur de Montreál, Montreál, Que´bec, Canada J Am Soc Nephrol 17: 920–922, 2006. doi: 10.1681/ASN.2006020135

argely from studies on isolated amphibian tissues— enzymes that can couple ATP hydrolysis to other reactions, skin and urinary bladder—we know that vasopressin so that much of the released energy is converted to more L (AVP) exerts its antidiuretic action by making the re- useful forms. For example, the enzyme adenylyl cyclase can sponsive epithelium more permeable to water and urea. The couple ATP hydrolysis to transfer phosphate groups to other nature of the membrane changes and the means by which the reactants forming phosphorylated intermediates including membrane changes are induced by the hormone remain to be PKA and the transcription factor cAMP responsive element elucidated. Of special interest is the finding of Orloff and (CRE)–binding protein (CREB) (7). Ј Ј Ј Ј Handler (1) that 3 5 cyclic adenosine monophosphate (3 5 Adenylyl cyclase is the effector enzyme responsible for con- cAMP), which has been implicated as an intracellular mediator verting ATP to cAMP. Class III adenylyl cyclases, which are of the action of several peptide hormones, mimics the action of phylogenetically closely related to guanylyl cyclases, are found AVP. Furthermore, increased tissue content of cAMP has been in prokaryotes and eukaryotes (8). G␣ (Figure 1) acts primarly noted after exposures of responsive tissues to vasopressin (2).” s as an allosteric activator (change in conformation) of adenylyl The above text was published more than 30 yr ago (3) and cyclase and helps the catalytic domain (C1 and C2) collapse this editorial, commenting on the manuscript of Li et al. in this around the substrate, whereas G␣ maintains the catalytic do- issue of JASN (4), describes new developments in the cAMP– i main in an open conformation (9,10). The plant diterpene for- protein kinase A (PKA) signaling pathways. skolin binds into the remnant pocket formed between C1 and cAMP C2 and allosterically activates most membrane-bound mamma- More than 20% of the human genome encodes proteins in- lian adenylyl cyclases. volved in transmembrane and in intracellular signaling pathways. The ubiquity of cAMP signaling in nature is remarkable because organisms as diverse as Paramecium, Dictyostelium, and The Most Common Downstream Effector of cAMP is PKA man have developed the ability to convert ATP into cAMP. The cAMP-PKA pathway is one of the most common and Invasive micro-organisms, such as Vibrio cholerae, Bordetella per- versatile signal pathways in eukaryotic cells and is involved in tussis, and Bacillus anthracis are also able to subvert their host’s the regulation of cellular functions in almost all tissues in physiology by either synthesizing their own secreted form of mammals, including regulation of cell cycle, proliferation, dif- the cyclases or various classes of activators of the enzyme (5,6). ferentiation and regulation of microtubule dynamics, chroma- tin condensation and decondensation, nuclear envelope disas- Catalytic Mechanisms of Mammalian Adenylyl Cyclase sembly and reassembly, as well as regulation of intracellular ATP, a nucleotide triphosphate composed of adenine, ri- transport mechanisms and ion fluxes (5). Because this single bose, and three phosphate groups, is the principal carrier of second messenger (the cAMP-PKA pathway) is involved in the chemical energy in cells. The terminal phosphate groups are regulation of so many diverse cellular processes, it must be highly reactive in the sense that their hydrolysis, or transfer highly regulated at several levels to maintain specificity. AVP- to another molecule, takes place with large amounts of free induced changes in cAMP concentration may vary in duration, energy. If the terminal phosphoanhydride bond of ATP were amplitude, and extension in the principal cells. In addition, to rupture by hydrolysis to produce adenosine diphosphate cAMP microdomains (a microdomain is represented as a red (ADP) and inorganic orthophosphate (Pi), energy would be domain in the right part of Figure 1) are shaped by adenylyl released in the form of heat. However, cells contain various cyclases that form cAMP, as well as phosphodiesterases (PDE) that degrade cAMP. Four PDE-4 genes (4A/B/C/D) give rise to 18 different isoforms in mammalian cells and one of these Published online ahead of print. Publication date available at www.jasn.org. may be specifically associated with aquaporin-2 (AQP2)–bear- Address correspondence to: Dr. Daniel G. Bichet, Centre de recherche, Hoˆpital du ing vesicles, a further specific compartmentalization of the Sacre´-Coeur de Montre´al, 5400 boul. Gouin Ouest, Montre´al, Que´bec, H4J 1C5 Canada. Phone: 514-338-2486; Fax: 514-338-2694; E-mail: [email protected] specific expression of AQP2 (11).

A-Kinase Anchoring Proteins, Further Compartmentalization A-kinase anchoring proteins (AKAP) target PKA to specific substrates and distinct subcellular compartments, providing further spatial and temporal specificity to the cAMP-PKA pathway. The activation of AKAP-anchored PKA by cAMP in discrete microdomains has been visualized in neonatal cardiomy- ocytes (12) and AKAP 18␦ (a splice variant of AKAP 18) has been found in principal cells of the inner medullary collecting duct in a distribution closely resembling the distribution of AQP2 (13), which could imply a role for AKAP 18␦ in the AQP2 shuttle exocytic process. In addition to the rapid signaling cascade described above, the long-term regulation of AQP2 expression involves the PKA- mediated phosphorylation of the transcription factor CREB (14,15). Figure 1. Schematic representation of the effect of vasopressin (AVP) to increase water permeability in the principal cells of Lithium Toxicity the collecting duct. AVP is bound to the V2 receptor (a G- protein–linked receptor) on the basolateral membrane. The ba- In this issue of JASN, Deen’s group used mouse cortical sic process of G-protein–coupled receptor signaling consists of collecting duct cells in culture to study and recapitulate some of three steps: a hepta-helical receptor that detects a ligand (in this the features of renal lithium toxicity in humans. This immor- case, AVP) in the extracellular milieu, a G-protein (Gϰs) that talized clonal collecting duct cell line, mpkCCDc14, was origi- dissociates into ␣ subunits bound to GTP and ␤␥ subunits after nally generated by Alain Vandewalle and colleagues (16). ϩ interaction with the ligand-bound receptor, and an effector (in These cells exhibit electrogenic Na transport stimulated by this case, adenylyl cyclase) that interacts with dissociated G- aldosterone and AVP, maintain AVP-inducible AQP2 expres- protein subunits to generate small-molecule second messen- sion, and produce large amounts of both AQP2 mRNA and gers. AVP activates adenylyl cyclase, increasing the intracellu- protein in response to physiologic concentrations of AVP (17). lar concentration of cAMP. The topology of adenylyl cyclase is characterized by two tandem repeats of six hydrophobic trans- As demonstrated before in rat kidney medulla (18), lithium membrane domains separated by a large cytoplasmic loop and caused marked downregulation of AQP2 expression. Surpris- ingly, this diminution/suppression of AQP2 expression terminates in a large intracellular tail. The dimeric structure (C1 and C2) of the catalytic domains is represented (see text). Con- seemed to be independent of cellular cAMP levels, which were version of ATP to cAMP takes place at the dimer interface. Two as or more elevated as compared with cells treated with 1-de- aspartate residues (in C1) coordinate two metal co-factors samino [8-D-arginine] vasopressin (dDAVP) but not subjected 2ϩ 2ϩ (Mg or Mn , represented here as two small black circles), to lithium treatment. Is the compartmentalization effect de- which enable the catalytic function of the enzyme (9). Adeno- scribed earlier responsible for this apparent dissociation be- sine is the large open circle and the three phosphate groups tween cAMP concentration and AQP2 expression? Kramer and (ATP) are the three small open circles. Protein kinase-A (PKA) colleagues have pioneered the use of “patch cramming,” where is the target of the generated cAMP. The binding of cAMP to a patch pipette containing a cAMP- or cyclic guanosine mono- the regulatory subunits of PKA induces a conformational change, causing these subunits to dissociate from the catalytic phosphate (cGMP)-gated ion channel in a membrane patch is subunits. These activated subunits (C) as shown here are an- introduced into a recipient cell (19). Endogenous cyclic-nucle- chored to an aquaporin-2 (AQP2)–containing endocytic vesicle otide-gated channels have also been used to measure cAMP in via an A-kinase anchoring protein (AKAP). The local concen- neurons (20). Concentrations of cAMP in discrete cellular do- tration and distribution of the cAMP gradient is limited by mains might be a better measurement of the cAMP-AKAP phosphodiesterases (PDE). Cytoplasmic vesicles carrying the signaling pathway. Alternatively, the major effect of lithium water channel proteins (represented as homotetrameric com- could be at a step distal to the generation of cAMP. Forskolin plexes) are fused to the luminal membrane in response to AVP, stimulation and expression of AKAP18␦ will be, in this context, thereby increasing the water permeability of this membrane. experiments to pursue. The dissociation of AKAP from the endocytic vesicle is not represented. Microtubules and actin filaments are necessary for vesicle movement toward the membrane. When AVP is not Could We Bypass the V2-Receptor Stimulation-Induced available, AQP2 water channels are retrieved by an endocytic Cascade to Insert AQP2 in the Luminal Membrane? process, and water permeability returns to its original low rate. Nitric oxide, atrial natriuretic factor, and the cGMP PDE AQP3 and AQP4 water channels are expressed constitutively at inhibitor sildenafil citrate (Viagra) have been shown to stimu- the basolateral membrane. late AQP2 membrane insertion in renal epithelial cells in vitro. However, no change in urine osmolality was detectable in sildenafil-treated Brattleboro rats compared with dehydrated controls, although there was a trend toward an increased osmolality after drug treatment (21). More recently, methyl-␤- 922 Journal of the American Society of Nephrology J Am Soc Nephrol 17: 920–922, 2006 cyclodextrin, a cholesterol-depleting drug, was shown to in- lates vasopressin-mediated water reabsorption by control- duce AVP-independent apical accumulation of AQP2 in the ling aquaporin-2. Biochem Soc Trans 33: 1316–1318, 2005 isolated perfused rat kidney (22). These new developments 12. Zaccolo M, Pozzan T: Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac could help bypass defective V2 receptors (X-linked nephrogenic diabetes insipidus [23]) or the complex signaling defect of myocytes. Science 295: 1711–1715, 2002 lithium-induced nephrogenic diabetes insipidus. 13. Henn V, Edemir B, Stefan E, Wiesner B, Lorenz D, Theilig F, Schmitt R, Vossebein L, Tamma G, Beyermann M, Acknowledgments Krause E, Herberg FW, Valenti G, Bachmann S, Rosenthal W, Klussmann E: Identification of a novel A-kinase anchor- Dr. Daniel G. 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See related article, “Development of Lithium-Induced Nephrogenic Diabetes Insipidus Is Dissociated from Adenylyl Cyclase Activity,” on pages 1063–1072.