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Signaling in

Ivana Y. Kuo1 and Barbara E. Ehrlich1,2

1Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520 2Department of Cellular and Molecular , School of Medicine, Yale University, New Haven, Connecticut 06520 Correspondence: [email protected]

SUMMARY

Signaling pathways regulate contraction of striated (skeletal and cardiac) and . Although these are similar, there are striking differences in the pathways that can be attributed to the distinct functional roles of the different muscle types. Muscles contract in response to depolarization, activation of G--coupled receptors and other stimuli. The actomyosin fibers responsible for contraction require an increase in the cytosolic levels of , which signaling pathways induce by promoting influx from extracellular sources or release from intracellular stores. Rises in cytosolic calcium stimulate numerous downstream calcium-de- pendent signaling pathways, which can also regulate contraction. Alterations to the signaling pathways that initiate and sustain contraction and relaxation occur as a consequence of exer- cise and pathophysiological conditions.

Outline

1 Introduction 8 failure 2 contraction 9 Smooth muscle types 3 Skeletal muscle fiber types and 10 The contractile process in smooth muscle 4 Malignant hyperthermia in skeletal muscle 11 Calcium sensitization 5 contraction 12 in disease 6 Exercise hypertrophy in cardiac muscle 13 Concluding remarks 7 Pathophysiological cardiac hypertrophy References

Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy Thorner Additional Perspectives on Signal Transduction available at www.cshperspectives.org

Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a006023 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a006023 1 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press I.Y. Kuo and B.E. Ehrlich

1 INTRODUCTION phosphorylation-dependent, and restoration of basal cal- cium levels or its phosphorylation status returns an actively Muscle can be subdivided into two general categories: stri- contracting muscle to a noncontractile state. Muscle-spe- ated muscle, which includes skeletal and cardiac muscles; cific signals modulate these processes, depending on the and nonstriated muscle, which includes smooth muscle type of muscle, its function, and the amount of force such as vascular, respiratory, uterine, and gastrointestinal required. muscles. In all muscle types, the contractile apparatus In all muscle cells, contraction thus depends on an in- consists of two main : and . Striated crease in cytosolic calcium concentration (Fig. 1). Calcium muscle is so called because the regular arrangement of has an extracellular concentration of 2–4 mM and a resting alternating actomyosin fibers gives it a striped appearance. cytosolic concentration of 100 nM. It is also stored inside This arrangement allows coordinated contraction of the cells within the sarcoplasmic (SR, referring to skeletal and whole muscle in response to neuronal stimulation through cardiac muscle) and (ER, referring a voltage- and calcium-dependent process known as exci- to smooth muscle) at a concentration of 0.4 mM (Boot- tation–contraction coupling. The coupling enables the man 2012). In striated muscle, the increase in calcium levels rapid and coordinated contraction required of skeletal is due to its release from the SR stores via re- muscles and the heart. Smooth muscle does not contain ceptor (RyRs). Neurotransmitters such as regular striations or undergo the same type of excitation– bind to receptors on the muscle surface and elicit a de- contraction coupling. Instead, it typically uses second mes- polarization by causing sodium/calcium ions to enter senger signaling to open intracellular channels that release through associated channels. This shifts the resting mem- the calcium ions that control the contractile apparatus. brane potential to a more positive value, which in turn These processes, in contrast to excitation–contraction cou- activates voltage-gated channels, resulting in an action pling, are slow and thus suitable for the slower and more potential (the “excitation” part). The stim- sustained contractions required of smooth muscle. The ulates L-type calcium channels (also known as dihydropyr- actomyosin contractile apparatus is both calcium- and idine receptors). In skeletal muscle, these are mechanically

ABStriated muscle Smooth muscle

Neuronal stimulus Depolarization Hormonal/neuronal stimulus (e.g., neurotransmitter release) (or window current) (e.g., vasopression, neurotransmitter)

Activation of neurotransmitter receptors Activation of Gq-coupled receptors

Depolarization Activation of Gq

Skeletal muscle Cardiac muscle

PLC Activation of L-type Activation of L-type Activation of L-type PIP IP and DAG Ca2+ channels Ca2+ channels Ca2+ channels 2 3

Tugging Opening of RyR IP3 binds IP3R and opens channel opens RyR via CICR

Increased intracellular Ca2+ Increased intracellular Ca2+

Activation of contractile apparatus Activation of contractile apparatus

Figure 1. Overview of muscle contraction signals in striated (A), and smooth (B) muscle.

2 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a006023 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling in Muscle Contraction coupled to the SR RyRs and open them directly. In cardiac actomyosin, which leads to contraction (Fig. 2C). Note muscle, calcium influx through the L-type channels opens that striated muscle contraction can also be regulated by RyRs via calcium-induced calcium release (CICR) (Boot- calcium-bound CaM and MLCK; however, this is not the man 2012). The RyR is a large tetrameric six-transmem- dominant mechanism. Finally, calcium and calcium-CaM brane-span calcium-release channel. Of the three RyR also bind to various other proteins in muscle cells, includ- subtypes, RyR1 is predominantly found in skeletal muscle ing the phosphatase calcineurin and protein kinases such (see review by Klein et al. 1996), and RyR2 is predominant- as CaMKIV, respectively. These regulate other cellular tar- ly found in cardiac muscle (Cheng et al. 1993). gets, including transcription factors such as NFAT and Smooth muscle also contains voltage-gated calcium CREB, which control gene expression programs that can channels and RyRs responsible for increases in intracel- have longer-term effects on muscle physiology. lular calcium concentration (see below). Depolarization These different calcium-release mechanisms all also causes L-type calcium channels to open, enabling calcium stimulate the pumping of calcium from the cytoplasm to enter down its concentration gradient into the cell (Fig. back into intracellular stores via the SR/ER calcium ATPase 1B). Opening of RyRs is usually associated with CICR. (SERCA) pump. The plasma membrane calcium ATPase As the intracellular calcium concentration rises, calcium (PMCA) pump and the sodium/calcium exchanger binds to RyRs, whose consequent opening further en- (NCX), both of which reside on the plasma membrane, hances the increase in cytoplasmic calcium concentration. can also remove calcium from the cytosol. Calcium dis- Another major mechanism controlling contraction in these sociates from C or as the cytosolic cells, however, involves a different tetrameric six-trans- calcium concentration decreases as a consequence, which membrane-span : the inositol 1,4,5-tri- terminates the contraction process. sphosphate (IP3) receptor (IP3R). Circulating hormones The main pathways promoting muscle relaxation in- (e.g., vasopressin and bradykinin) and neurotransmitters volve the second messengers cAMP and cyclic guanosine released by sympathetic (e.g., endothelin and nor- monophosphate (cGMP). cAMP is generated by adenylyl epinephrine) act through G-protein-coupled receptors cyclases, downstream from the b-adrenergic GS-coupled (GPCRs) to generate the second messenger IP3 via acti- receptor, which is activated by noradrenaline. Note that vation of phospholipase C (PLC). IP3 binds to and opens the cAMP pathway generally promotes contraction in car- IP3Rs on the ER/SR, causing the calcium release that drives diac muscle; however, in smooth muscle, activation of contraction. IP3Rs are present in both skeletal and cardiac cAMP causes relaxation. The cGMP pathway can be acti- muscle; however, they do not contribute significantly to the vated either by nitric oxide (NO) or natriuretic peptides excitation–contraction coupling in striated muscle. Note (NPs). In the case of blood vessels and other smooth mus- that both RyRs and IP3Rs are stimulated by low concentra- cles, NO produced by endothelial NO synthase (eNOS) tions of cytoplasmic calcium but close when the concen- diffuses across the membrane to activate solu- tration gets higher, showing bell-shaped response curves ble guanylyl cyclase (sGC), which in turn increases levels (Bezprozvanny et al. 1991; Finch et al. 1991). of cGMP. NPs, such as atrial (ANP, released by the heart Once intracellular calcium levels are raised, calcium atria under high ), (BNP, primarily binds to either on actin filaments (in striated released by the heart ventricle), and c-type (CNP, mainly muscle) or calmodulin (CaM), which regulates myosin fil- involved in pathological conditions, and released by the aments (in smooth muscle). In striated muscle, calcium vascular and central ), instead bind to trans- causes a shift in the position of the troponin complex on membrane guanylyl cyclase, whose intracellular domain actin filaments, which exposes myosin-binding sites (Fig. possesses the enzymatic activity (Nishikimi et al. 2011). 2A). Myosin bound by ADP and inorganic phosphate (Pi) The cAMP and cGMP generated act via the protein ki- can then form cross-bridges with actin, and the release of nase PKA and PKG on the contractile process in multiple ADP and Pi produces the power that drives contrac- ways: (1) their phosphorylation of calcium pumps leads tion. This force causes the thin actin filament to slide past to increased activity; (2) activation of MLC phosphatase the thick myosin filament and shortens the muscle. Bind- (MLCP) by PKG antagonizes MLCK; and (3) both PKA ing of ATP to myosin then releases myosin from actin, and and PKG cause a reduction in the sensitivity of the con- myosin hydrolyzes ATP to repeat the process (Fig. 2B). tractile machinery by inhibiting the GTPase RhoA (this In smooth muscle, by contrast, calcium binds to CaM, increases MLCP activity and causes MLC dephosphoryla- which then interacts with myosin light-chain kinase tion and muscle relaxation). The levels of cAMPand cGMP (MLCK), causing it to phosphorylate the myosin light-chain are in turn regulated through their degradation by phos- (MLC) at S19 or Y18. The phosphorylated MLC then phodiesterases to yield the inactive metabolites 5′-AMP forms cross-bridges with actin, producing phosphorylated and 5′-GMP.

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A B

1. Actin 1. Ca2+ binds troponin C, exposing myosin-binding sites on actin. Myosin Actin

Troponin Actin Tropomyosin ADP complex 6. ADP is released. 2. ATP binds to myosin.

Ca2+ ADP Troponin C ATP 5. Pi is released; myosin head changes confor- 3. ATP is hydrolyzed. 2+ 2+ mation to produce the Pi 2. Ca Ca Myosin is in the power stroke. Filaments cocked state. slide past each other.

Myosin ATP ADP + Pi ADP + Pi Myosin-binding 4. Cross-bridge forms and myosin sites on actin are exposed. binds to a new position on actin.

C Ca2+ CaM

Ca2+ CaM

ATP MLCK MLC MLC -P

Actin Actin

P-Actomyosin MLC -P

Actomyosin Pi Contraction MLC

Figure 2. Calcium triggers contraction in striated muscle. (A) Actomyosin in striated muscle. (1) Striated muscle in the relaxed state has tropomyosin covering myosin-binding sites on actin. (2) Calcium binds to troponin C, which induces a conformational change in the troponin complex. This causes tropomyosin to move deeper into the actin groove, revealing the myosin-binding sites. (B) Cross-bridge cycle in striated muscle. (1) Calcium binds to troponin C, causing the conformational shift in tropomyosin that reveals myosin-binding sites on actin. (2) ATPthen binds to myosin. (3) ATP is then hydrolyzed. (4) A cross-bridge forms and myosin binds to a new position on actin. (5)Piis released and myosin changes conformation, resulting in the power stroke that causes the filaments to slide past each other. (6) ADP is then released. (C) Contraction in smooth muscle. In smooth muscle, calcium binds to calmodulin and causes the activation of myosin light chain (MLC) kinase (MLCK). This phosphorylates MLC, which then binds to actin to form phosphorylated actomyosin, enabling the cross-bridge cycle to start.

Below, we examine the key differences between the sig- 2 SKELETAL MUSCLE CONTRACTION naling mechanisms controlling contraction of skeletal, cardiac, and smooth muscle, and how these relate to their Skeletal muscles comprise multiple individual muscle fi- differing functions. In addition, we discuss the changes to bers that are stimulated by motor stemming from the signaling pathways that occur as a consequence of ex- the . They are grouped together to form “mo- ercise and pathological situations. tor units” and more than one type of muscle fiber can be

4 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a006023 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling in Muscle Contraction present within each . Muscle fibers can be di- are concentrated (Fig. 3A). The transfer of information vided into fast- and slow-twitch muscles. Fast-twitch mus- between the and muscle is mediated by the release cles use glycolytic and are recruited for phasic of acetylcholine from the motor , which diffuses activity (an active contraction). Slow-twitch muscles (also across the synaptic cleft, and binds to and activates the known as red muscles) are rich in myoglobin, mitochon- ligand-gated, nicotinic acetylcholine receptors (nAChRs) dria, and oxidative and specialized for sustained on the endplate. Activation of the nAChR leads to an influx or tonic activity. See Schiaffino and Reggiani (2011) for a of cations (sodium and calcium) that causes depolarization more complete discussion of skeletal muscle types and the of the muscle cell membrane. This depolarization in turn types of myosin isoforms that make up fast- and slow- activates a high density of voltage-gated sodium channels twitch muscles. on the muscle membrane, eliciting an action potential. The (NMJ) that connects skel- The action potential runs along the top of the mus- etal muscle with the nerves that innervate them consists cle and invades the T-tubules (specialized invaginations of of three distinct parts: the distal motor nerve ending, the the membrane containing numerous ion channels). The synaptic cleft, and the postsynaptic region, located on the opening of voltage-gated sodium channels activates L- muscle membrane. Motor neurons branch into multiple type voltage-gated calcium channels lining the T-tubule. termini, which are juxtaposed to motor endplates, special- A conformational change in these enables release of cal- ized regions of muscle where neurotransmitter receptors cium on the closely apposed SR via activation of RyR1.

A B

Nerve ending 2+ Action Ca potential propagates Neuromuscular Na+ channels junction K+ p38MAPK CaMKIV AMPK MLCK ACh T-tubule Synaptic AChR Na+ CREB cleft

Na+ SR PGC1α RyR

L-type Ca2+ Ca2+ channel Ca2+ FOXO MEF2 NRF PPAR

SERCA Mitochondrial biogenesis: and lipid homeostasis changes Contraction Promotes Actomyosin relaxation Cytoplasm

Figure 3. Skeletal muscle contraction and changes with exercise. (A) Neurotransmitter (acetylcholine, ACh) released from nerve endings binds to receptors (AChRs) on the muscle surface. The ensuing depolarization causes sodium channels to open, which elicits an action potential that propagates along the cell. The action potential invades T- tubules and causes the L-type calcium channels to open, which in turn causes ryanodine receptors (RyRs) in the SR to open and release calcium, which stimulates contraction. Calcium is pumped back into the SR by (SR/ER calcium ATPase SERCA) pumps. The decreasing cytosolic calcium levels cause calcium to disassociate from troponin C and, consequently, tropomyosin reverts to a conformation that covers the myosin-binding sites. (B) Signaling in exercised skeletal muscle. Both calcium and calcium-independent signals stimulate the transcriptional coactivator PGC1a. This activates a number of transcription factors that regulate genes associated with mitochondrial biogenesis, glucose, and lipid homeostasis.

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Calcium then binds to troponin as described above, initi- to dissociate from SERCA. The FKBPs ating the contraction process. Calcium-bound CaM also are immunophilins that bind to immunosuppressants activates MLCK, whose phosphorylation of the MLC such as rapamycin and FK506. FKBP12 and FKBP12.6 changes cross-bridge properties. This modulates the tropo- have differing expression levels in , but both nin-dependent contraction, although there is no effect on bind all three forms of the RyR and stabilize its closed state. the ATPase activity of MLC. MLC phosphorylation instead Collectively, these calcium-dependent differences between enhances force development at submaximal saturating cal- fast- and slow-twitch muscle fibers, in addition to differ- cium concentrations (see below). The phosphate group is ences in the myosin isoform used and the number of mi- subsequently removed by protein phosphatase 1 (PP1). tochondria, account for the different functional outputs of the two muscle fiber types. Long-term exercise causes a general shift in muscle fiber 3 SKELETAL MUSCLE FIBER TYPES AND EXERCISE type from slow twitch to fast twitch. It induces a number of Skeletal muscle is plastic. Exercise can lead to pronounced changes, including altered expression and activity of mem- changes in its metabolic properties and, sometimes, a brane transporters and mitochondrial metabolic enzymes, change in the fiber type. Physical differences between together with increased blood supply to skeletal muscle fast- and slow-twitch muscles underlie the functional roles (Hardie 2012). These, in turn, enhance the oxidative ca- of these fibers, including the type of myosin used and dif- pacity and increase expression of enzymes preventing dam- fering resting calcium levels. The free calcium level is two- age by reactive species (ROS). One major signaling fold higher in slow-twitch muscle, even though the SR pathway is through the peroxisome-proliferator-activated volume is greater. The level of MLC phosphorylation is receptor (PPAR) g coactivator (PGC) 1a (Fig. 3B). PGC1a higher in fast-twitch muscle, however, because of higher coactivates a number of transcription factors that regu- levels of expression of MLCK (Bozzo et al. 2005). The force late genes important for muscle function. These include enhancement produced by MLC phosphorylation, under PPARs (which regulate glucose and lipid homeostasis, pro- submaximal saturating calcium concentrations, counter- liferation, and differentiation), nuclear respiratory factors acts the reduction in force caused by fatigue in fast-twitch (NRFs, which regulate metabolism and mitochondrial muscle fibers (Schiaffino and Reggiani 2011). biosynthesis), myocyte enhancer factor 2 (MEF2, which Fast- and slow-twitch fibers also have different calcium- is involved in development and hematopoesis), and Fork- sequestering and -buffering systems. Different SERCA iso- head box O (FoxO) family transcription factors (which forms are present: SERCA2A is the main isoform in slow- counter oxidative stress and promote cell-cycle arrest and twitch muscle fibers, whereas SERCA1A is expressed in apoptosis) (Handschin and Spiegelman 2006; Ronnebaum fast-twitch muscle fibers. Similarly, different cytosolic cal- and Patterson 2010). In addition to PGC1a, calcium-de- cium buffers are expressed. (CSQ) is the pendent processes are also involved. Rises in cytosolic main SR-luminal calcium-buffering protein. It is a high- calcium result in the activation of calcineurin, which then capacity, low-affinity calcium-binding protein that binds dephosphorylates NFAT. Translocation of NFAT to the nu- calcium cooperatively (Campbell et al. 1983). When the cleus results in activation of slow-fiber gene expression. muscle is at rest, the SR is primed to release large amounts Rises in nuclear calcium levels also cause calcium-depen- of calcium, because CSQ is polymerized, which reduces its dent signaling molecules to become active. These include ability to bind calcium. In cardiac muscle, only CSQ2 is the phosphorylation of histone deacetylases (HDACs) by expressed. In skeletal muscle, CSQ1 and CSQ2 are found in nuclear calmodulin-dependent protein kinase. HDACs re- slow-twitch muscle fibers, but only CSQ1 is found in fast- press transcription by causing DNA to be tightly wrapped twitch muscle fibers. The two isoforms differ in their car- around histones. Removal of HDACs enables transcrip- boxy-terminal tail; functionally, CSQ1 reduces the activity tion factors such as MEF2 to bind and enable induction of RyR1, whereas CSQ2 increases the open probability of of genes encoding proteins found in slow fibers (Liu et al. RyR1 and RyR2 (Wei et al. 2009). 2005). Other differences between the muscle fiber types in- As mentioned above, exercise induces an increase in clude posttranslational modifications such as phosphory- the levels of mitochondrial metabolic enzymes to com- lation of RyR by PKA, and interactions between RyR and pensate for the increased metabolic demand on skeletal other proteins, such as CaM and FK506-binding protein muscle. Unsurprisingly, PGC1a is a potent stimulator of (FKBP) 12 and FKBP12.6. Phosphorylation of RyR by mitochondrial biogenesis (see review by Olesen et al. 2010). either PKA or CaMKII fully activates the channel. PKA This was shown elegantly by experiments in which over- and CaMKII can also phosphorylate phospholamban, a expression of PGC1a in white, glycolytic skeletal muscle protein that inhibits SERCA; phosphorylation causes could turn it into red, oxidative muscle by increasing the

6 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a006023 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling in Muscle Contraction levels and activity of a number of mitochondrial proteins of sodium and calcium ions. The action potential then (Lin et al. 2002; Wenz et al. 2009). These proteins include traverses to the cardiac myocytes, where it invades the most components of the mitochondrial respiratory chain T-tubule. However, unlike skeletal muscle, where L-type and ATP synthase, as well as several enzymes in the Krebs calcium channels are directly coupled to RyRs, in cardio- cycle and enzymes involved in fatty acid oxidation. myocytes the influx of calcium across the plasma mem- brane elicits calcium release from the SR via RyRs by CICR (Fig. 4B). The predominant isoform in the heart is 4 MALIGNANT HYPERTHERMIA RyR2. As in skeletal muscle, contraction is controlled by IN SKELETAL MUSCLE phosphorylation of troponin but can also be modulated by Mutations in RyR and CSQ isoforms cause malignant calcium-CaM and MLCK. Mice with a nonphosphory- hyperthermia, demonstrating the importance of proteins latable MLC in ventricular myocytes display depressed involved in in skeletal muscle. The mu- contractile function and develop atrial hypertrophy and tations in RyR1 appear to increase its open probability dilatation (Sanbe et al. 1999). when levels of luminal calcium are low and account for Catecholamines, such as adrenaline and noradrenaline, the majority of malignant hyperthermia cases (80%); the act on b-adrenergic receptors (metabotropic GPCRs) to remainder are caused by mutations to CSQ1. release cAMP that in turn activates PKA. PKA can be In the case of RyR1 mutations, volatile anesthetics (in- viewed as a primary regulator of the contractile pathway, as haled anesthetics such as isoflurane or halothane) lead to a it phosphorylates a number of targets, including L-type rapid opening of RyR1 and an uncontrolled release of cal- calcium channels and RyRs. In most cases, phosphory- cium from the SR, which in turn leads to sustained skeletal lation of these proteins increases calcium release (for muscle contraction (Robinson et al. 2006). In response to example, phosphorylation of RyR increases its open prob- the elevated calcium levels, there is activation of SERCA to ability), and thus the outcome is to stimulate contraction pump calcium, using ATP, back into the SR. However, the (Ibrahim et al. 2011). Another target of PKA is phospho- continual activation of SERCA consumes excessive ATP, lamban (an inhibitor of SERCA), which, when phosphor- leading to hypermetabolism. This then leads to a drop in ylated, loses its inhibitory effect on SERCA. ATP levels, acidosis, tachycardia, and an abnormal increase in body temperature. These symptoms can be treated with 6 EXERCISE HYPERTROPHY IN CARDIAC MUSCLE , an inhibitor of the RyR signaling pathway. The mutations in RyR1 associated with malignant hyperther- Cardiac hypertrophy is an abnormal enlargement of the mia are clustered in three hot spots on the 500 kDa protein heart that occurs because of increases in cell size and pro- (Lanner et al. 2010). The first cluster is near the amino liferation of nonmuscle cells. These changes can either terminus and the second cluster is in the middle of the be beneficial (e.g., exercised ), in which changes are protein. The third cluster lies in the carboxy-terminal re- correlated with increased contractility, or detrimental, in gion surrounding the channel-forming domains. How mu- which changes lead to decreased contractility and subse- tations in all three regions exert similar effects is yet to be quent . determined. Exercised hearts develop a form of mild cardiac hy- Mutations in CSQ can also result in malignant hyper- pertrophy that does not lead to cardiac failure. The main thermia. A lack of buffering causes uncontrolled calcium structural changes include a thickening of the ventricle wall, transients that lead to lethal malignant hyperthermia in which leads to increased contractility and thus a greater response to heat stress and volatile anesthetics (Dainese ability to pump blood. Within myocytes, expression of the et al. 2009). a myosin heavy chain increases, which leads to high ATPase activityand increased contractility (Fig. 4B). Varioussignals are involved, including growth factors such as insulin-like 5 CARDIAC MUSCLE CONTRACTION growth factor (IGF1), vascular endothelial growth factor In cardiac muscle, depolarization starts in the pacemaker (VEGF), and hepatocyte growth factor (HGF) (Fig. 4B) cells (modified cardiac myocytes that set the heart rate and (Hemmings and Restuccia 2012). There is increased signal- are rich in signaling molecules) in the , ing through the phosphoinositide 3 kinase (PI3K)/Akt which is innervated by both parasympathetic and sympa- pathway, which leads to proliferation and growth of cardio- thetic nerves. The external stimuli modulate the activity of myocytes (Matsui et al. 2003). Transcription factors up- the pacemaker cells—they undergo spontaneous self-de- regulated in exercised hearts include GATA4, which regu- polarization to produce action potentials. This is achieved lates genes involved in myocardial differentiation. Other by a slow leak of ions and a concurrent influx pathways, such as the calcineurin/NFAT pathway are

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A Adrenaline, noradrenaline β- Depolarization βγ AC Contraction- G α G s ATP promoting pathway

cAMP

SR L-type PKA Ca2+ channel

RyR ClCR

SERCA Relaxation- promoting Ca2+ pathway

Ca2+

PKA Contraction

-P Phospholamban

B External factors: IGF1, VEGF, HGF

Signaling pathways:

PI3K Calcinuerin Akt NFAT

Transcription factors PGC1α GATA4

Proliferation Growth Myocardial differentiation

Figure 4. Cardiac muscle contraction and changes with exercise. (A) Cardiac muscle contraction can occur as a consequence of calcium entry through L-type calcium channels, which activate (RyR) channels in the SR. Alternatively, b-adrenergic receptors on the cell membrane lead to activation of adenylyl cyclase (AC), which stimulates PKA. This can promote contraction by phosphorylating RyR and L-type calcium channels or relaxation by phosphorylating the SERCA pump inhibitor phospholamban. (B) Changes with exercise lead to an activation of the PI3K/Akt pathway, and a down-regulation of NFATand calcinurin. down-regulated (Oliveira et al. 2009). Cardiac muscle, like 7 PATHOPHYSIOLOGICAL CARDIAC skeletal muscle, consumes tremendous amounts of ATP. HYPERTROPHY Thus, PGC1a is also up-regulated in exercised hearts, facil- itating transcription of metabolic and oxidative genes (Ven- The main pathways driving pathological cardiac hypertro- tura-Clapier et al. 2007; Watson et al. 2007). phy are overstimulation of the sympathetic nervous system,

8 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a006023 Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling in Muscle Contraction increased oxidative stress, and inflammatory signaling (Ba- FKBP12.6 (Andersson and Marks 2010). Both of these lakumar and Jagadeesh 2010). These collectively lead to changes result in increased RyR activity. Moreover, muta- induction of fetal isoforms of heart proteins and a corre- tions in RyR2 that result in leaky channels have been linked sponding decrease in adult forms (Chien 1999), including to catecholaminergic polymorphic ventricular tachycardia the myosin heavy chain (see below). The signals responsible (CPVT) and arrhythmogenic right ventricular dysplasia include the GPCR agonist endothelin 1, peptide growth type 2. factors such as platelet-derived growth factor (PDGF), epi- Mutations in CSQ2 cause CPVT (Postma et al. 2002) dermal growth factor (EGF), and cytokines such as cardio- by lowering buffering capacity within the SR, which results trophin and leukemia inhibitory factor (LIF). Mechanical in premature calcium release and thus . Anoth- stress can also induce hypertrophy. In each case, activation er important modulator of RyRs is junctin. Its levels are of theERKmitogen-activatedprotein kinase(MAPK)path- reduced in heart failure, which may be a compensatory way (Morrison 2012) is often observed in hypertrophy and mechanism to increase contractility (Pritchard and Kranias leads to regulation of transcription factors that alter expres- 2009). sion of the myosin heavy chain, IP3R2, and other proteins Heart failure also leads to up-regulation of molecules (see below). that may have a protective function. One pathway isthrough In hypertrophy, paracrine and autocrine neurohor- cGMP, which promotes relaxation. The cGMP pathway is monal factors that activate the heterotrimeric G protein regulated by cGMP-targeted phosphodiesterases, of which Gq, and consequently PLCb, are released. This results one, PDE5A, looks to be a promising target for protective in an increase in cytosolic calcium levels and activation therapy against hypertrophy. of PKC by diacylglycerol (DAG) as well as activation of CaMKII (Mishra et al. 2010). The importance of the Gq 9 SMOOTH MUSCLE TYPES pathway in hypertrophy has been shown in studies of trans- genic mice: mice overexpressing Gq have heart failure Smooth muscle is found lining the walls of various organs (D’Angelo et al. 1997), whereas mice with reduced Gq levels and tubular structures in the body, including the intestine, are protected against hypertrophy (Wettschureck et al. bladder, airway, uterus, blood vessels, and stomach. It re- 2001). There is also a switch from the a form of the myosin ceives neural innervation from the autonomic nervous heavy chain to the fetal b isoform (Miyata et al. 2000). This system, and its contractile state is also controlled by hor- has a lower ATPase activity and a lower rate of contraction. monal and autocrine/paracrine stimuli. Smooth muscle Other changes include increased SERCA2A activity (Ha- can be divided into two types: unitary and multiunit senfuss et al. 1994; Meyer et al. 1995), up-regulation of smooth muscles. In unitary smooth muscle, individual IP3R2 (Harzheim et al. 2010), and changes to a neuronal smooth muscle cells are coupled to neighboring cells by calcium sensor (NCS1). NCS1 is a calcium-binding protein gap junctions. These gap junctions permit cell-to-cell pas- that also interacts with IP3R (Schlecker et al. 2006). sage of small molecules such as ATPand ions. These include those mobilized in response to electrical signals causing depolarization, which enable the whole area (known as a 8 HEART FAILURE ) to coordinate activity. In contrast, in multiunit The structural organization of the T-tubules breaks down smooth muscle, cells are not coupled to each other and are in heart failure. This breakdown, caused by myocardial intermingled with . Smooth muscle can insults (such as causing ischemia) undergo tonic (sustained) or phasic contractions. In the among other factors, leads to impaired contractility owing case of vascular smooth muscle, a sustained contraction is to reduced, asynchronous, and chaotic calcium release. required to provide vessel tone. This enables the regulation Several signaling pathways are compromised in heart fail- of blood flow. Blood vessels are divided into the larger di- ure. Initially, there can be reorganization of the b-adrener- ameter conduit vessels (e.g., the thoracic aorta) and the gic system. Activation of the b2-adrenergic receptor is smaller diameter resistance vessels. The resistance blood normally limited to the T-tubule, whereas in heart failure, vessels display a myogenic response, in which increasing there is a redistribution of the receptor across the entire pressures over the physiological range (70–100 mmHg) plasma membrane (Nikolaev et al. 2010). With chronic result in a sustained contractile state. However, overcon- adrenergic activation, the hyperphosphorylation of RyRs striction of the vessels leads to (see below). results in leaky RyR channels, leading to a reduction of SR Other smooth muscle, such as that found in the gut, in- calcium and, thus, weaker contractions. cluding the stomach, small intestine, or gall bladder, shows Other alterations to RyR2 that are observed include variable tone and rhythmic contractions known as slow increased nitrosylation and loss of the regulatory protein waves.

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10 THE CONTRACTILE PROCESS population of the L-type channels is always open. An alter- IN SMOOTH MUSCLE natively spliced high-voltage-gated form of T-type chan- nels may also contribute to calcium influx (Kuo et al. 2011), The important distinction between striated muscle and along with stretch-activated channels residing on the plas- smooth muscle is that calcium mediates contraction by ma membrane, such as TRPC6. regulating the availability of actin filaments in striated mus- In stomach muscle, the rhythmic contractions are due cle, whereas in smooth muscle MLC is the target (Fig. 5). to the activity of pacemaker cells, but activation of voltage- The source of the increase in cytosolic calcium levels can be gated calcium channels can trigger calcium entry and con- extracellular or intracellular, or a combination of the two. traction. Sympathetic nerves run along the vascular smooth In the case of tonic constriction of blood vessels, a constant muscle and can release stimuli such as acetylcholine, nor- supply of calcium comes from influx via the L-type calcium epinephrine, angiotensin, and endothelin. Moreover, circu- channels. The resting membrane potential of smooth mus- lating blood factors such as cytokines and diffusible factors cle (between 250 and 240 mV) is such that it lies in an such as nitric oxide can also act on receptors in the plasma overlap (the window current) between the activation and membrane or cross the plasma membrane, respectively, to inactivation curves of the L-type channel. Thus a small regulate pathways controlling intracellular calcium levels.

Agonist (e.g., ATP, vasopressin)

ANP GPCR 2+ NO L-type Ca channel

GC Rho PLCβ PIP Gq 2

GTP cGMP IP3 PKC DAG Ca2+ GC ROCK IP3R

PKG ER store

CPI-17 Ca2+

Relaxation CaM

MLC MLCP MLCK

MLC -P

Contraction

Figure 5. Smooth muscle contraction. Calcium released by L-type calcium channels or IP3Rs downstream from Gq- coupled cell-surface receptors causes smooth muscle contraction. It binds to calmodulin (CaM) and the resulting complex stimulates myosin light-chain (MLC) kinase (MLCK). This phosphorylates MLC to promote contraction. A RhoA/ROCK pathway and a diacylglycerol (DAG) pathway contribute to calcium sensitization by altering the phosphorylation status of myosin light-chain phosphatase (MLCP). Relaxation is mediated through the cGMP/ PKG pathway downstream from nitric oxide (NO) and agonists such as atrial natriuretic peptide (ANP).

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The activation of receptor-operated channels (ROCs) also pathways. First, ROCK stimulates phosphorylation of causes calcium influx, which enables additional calcium MYPT1 (Feng et al. 1999). This can be direct, at T695 or release from intracellular stores. GPCRs activate PLCb to T853, with a preference for T853. Alternatively, it can phos- generate IP3, which releases calcium via IP3Rs. In vascular phorylate another kinase, zipper-interacting protein kinase smooth muscle and the circular smooth muscle of the gut, (ZIPK, also known as DAPK3), which phosphorylates the main isoform is IP3R1. Note, however, that there is some MYPT1 primarily at T695 (Kiss et al. 2002). ZIPK also heterogeneity. In longitudinal smooth muscle of the gut, phosphorylates MLC at T18/S19. Phosphorylation of RyRs, rather than IP3Rs, are expressed. Agonists such as MYPT1 interferes with binding of MLCP to MLC, and cholecystokinin bind to the GPCR cholecystokinin A recep- thus is believed to decrease phosphatase activity. ROCK tor (CCK-AR), which activates phospholipase A2, which in can also phosphorylate CPI-17 (MacDonald et al. 2001). turn produces arachidonic acid. Arachidonic acid (AA) can The preference for the MYPT1 or CPI-17 pathway de- also be generated through the cleavage of DAG. AA activates pends on the type of smooth muscle. Whereas MYPT1 is chloride channels, which depolarize the cell membrane, ubiquitously expressed in smooth muscle, CPI-17 is differ- enabling the opening of voltage-gated calcium channels entially expressed. Moreover, RhoA and associated proteins and an initial influx of calcium. This calcium can either are expressed at lower levels in phasic smooth muscle com- act directly on the RyR causing CICR or enable the release pared with tonic smooth muscle (Patel and Rattan 2006). of cyclic ADP ribose, which interacts with RyRs to enhance Note that PKC can also phosphorylate CPI-17 to prevent CICR. MLCP activity. Within resistance , an increase in In all smooth muscle, calcium-bound CaM then binds vascular pressure also activates the RhoA pathway; how- to MLCK, stimulating phosphorylation of MLC, which ever, the signaling intermediates linking the change in vas- leads to muscle contraction. The necessity for MLCK has cular pressure and the activation of RhoA remain unknown been shown in MLCK-knockout mice, in which smooth (Cole and Welsh 2011). muscle MLC cannot be phosphorylated by other kinases (He et al. 2008; Zhang et al. 2010). The dephosphorylation 12 VASCULAR SMOOTH MUSCLE IN DISEASE of MLC is catalyzed by MLCPand a complex of the myosin- targeting protein MYPT1 and the phosphatase PP1 and Smooth muscle cells are remarkably plastic, altering their results in relaxation. phenotype in response to conditions such as vascular in- jury, altered blood flow conditions, or disease states. The changes in phenotype that can occur include cell prolifer- 11 CALCIUM SENSITIZATION ation, apoptosis, and cell migration and are induced by Calcium sensitization is an essentially calcium-indepen- many factors, including cytokines and growth factors, me- dent process that enables the amount of constriction in chanical forces, neuronal stimuli, and genetic factors. Here smooth muscle to be tuned by an alteration in the sensi- we limit our discussion to hypertension. tivity of MLC to calcium (Fig. 5). This process enables the In hypertension, there is often a change in the sympa- muscle to sustain a contraction once the initial calcium thetic nervous system and the renin–angiotensin system transient has dissipated. There are two mechanisms for that leads to increased blood pressure. Angiotensinogen calcium sensitization: a DAG-PLC-PKC pathway and a is converted to angiotensin I by renin, which in turn is RhoA pathway (Lincoln 2007). converted to angiotensin II by angiotensin-converting en- Diacylglycerol (DAG) is produced by PLCb down- zyme (ACE). Increased circulating angiotensin II acts on stream from certain GPCRs and activates the conventional the angiotensin receptors (AT1 and AT2), which, when and novel protein kinase C (cPKC and nPKC), but not activated, cause increased peripheral resistance. The con- atypical PKC (aPKC) (Steinberg 2008). PKC has a variety sequence for smooth muscle cells is they become hy- of downstream targets, such as MLCK and C-kinase poten- percontractile. Treatments include ACE inhibitors (which tiated protein phosphatase 1 inhibitor, molecular mass inhibit the conversion of angiotensin I to angiotensin 17 kDa (CPI-17), both of which enhance constriction. II), a1-adrenergic antagonists (which block the AT1 and CPI-17 is a smooth-muscle-specific inhibitor of MLCP AT2 GPCRs), and calcium channel blockers (such as dihy- that binds to its catalytic subunit and inhibits phosphatase dropyridines, which inhibit the voltage-gated calcium activity, allowing contraction to persist. channels). All of these treatments aim to reduce the con- Several agonists, including angiotensin II, norepine- tractility of smooth muscle. Interfering with downstream phrine, and endothelin, activate the small G protein targets such as RhoA signaling in hypertensive animals has RhoA. RhoA in turn activates Rho kinase (ROCK), which also been shown to be effective (Uehata et al. 1997; Seko can mediate calcium sensitization through two main et al. 2003; Moriki et al. 2004).

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The sustained contractile state of vascular smooth mus- exercised and pathological striated muscle provides new cle is associated with the activation of calcium-dependent avenues to modulate muscles in a therapeutic setting. It is transcription factors. These include SRF, FOS, NFAT, also apparent that many signaling proteins in both smooth and CREB. SRF, which is activated by the RhoA pathway, and striated muscles are activated by changes in cytosol- promotes the expression of genes encoding components ic calcium levels, and these signaling pathways often lead of the contractile apparatus. Calcium-stimulated CaMKII to alterations in gene expression. Because we now have a activates and causes the translocation of CaMKIV to the better appreciation of the changes that occur to the con- nucleus, where it can activate CREB, which promotes tran- tractile apparatus under pathophysiological conditions, scription of components of the contractile apparatus and this knowledge can be harnessed to allow us to treat disease other targets. However, CaMKII can also activate a phos- strategically. phatase that dephosphorylates and thus inactivates CREB (Matchkov et al. 2012). NFAT is activated on dephosphor- ACKNOWLEDGMENTS ylation by calcium-activated calcineurin, which induces genes associated with proliferation and migration. Research in the Ehrlich Laboratory is supported by Nation- NO produced by eNOS in endothelial cells protects al Institutes of Health funds. 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Signaling in Muscle Contraction

Ivana Y. Kuo and Barbara E. Ehrlich

Cold Spring Harb Perspect Biol 2015; doi: 10.1101/cshperspect.a006023

Subject Collection Signal Transduction

Cell Signaling and Stress Responses Second Messengers Gökhan S. Hotamisligil and Roger J. Davis Alexandra C. Newton, Martin D. Bootman and John D. Scott Protein Regulation in Signal Transduction Signals and Receptors Michael J. Lee and Michael B. Yaffe Carl-Henrik Heldin, Benson Lu, Ron Evans, et al. Synaptic Signaling in Learning and Memory Cell Death Signaling Mary B. Kennedy Douglas R. Green and Fabien Llambi Reproduction Signaling Networks that Regulate Cell Migration Sally Kornbluth and Rafael Fissore Peter Devreotes and Alan Rick Horwitz Signaling in Lymphocyte Activation Signaling Networks: Information Flow, Doreen Cantrell Computation, and Decision Making Evren U. Azeloglu and Ravi Iyengar Signaling in Muscle Contraction Signal Transduction: From the Atomic Age to the Ivana Y. Kuo and Barbara E. Ehrlich Post-Genomic Era Jeremy Thorner, Tony Hunter, Lewis C. Cantley, et al. Toll-Like Receptor Signaling Signaling by the TGFβ Superfamily Kian-Huat Lim and Louis M. Staudt Jeffrey L. Wrana Signaling Pathways that Regulate Cell Division Subversion of Cell Signaling by Pathogens Nicholas Rhind and Paul Russell Neal M. Alto and Kim Orth

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