Downloaded from http://cshperspectives.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Signaling in Muscle Contraction 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 Physiology, School of Medicine, Yale University, New Haven, Connecticut 06520 Correspondence: [email protected] SUMMARY Signaling pathways regulate contraction of striated (skeletal and cardiac) and smooth muscle. 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-protein-coupled receptors and other stimuli. The actomyosin fibers responsible for contraction require an increase in the cytosolic levels of calcium, 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 Heart failure 2 Skeletal muscle contraction 9 Smooth muscle types 3 Skeletal muscle fiber types and exercise 10 The contractile process in smooth muscle 4 Malignant hyperthermia in skeletal muscle 11 Calcium sensitization 5 Cardiac muscle contraction 12 Vascular smooth muscle 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 proteins: actin and myosin. 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 endoplasmic reticulum (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 ryanodine re- muscles and the heart. Smooth muscle does not contain ceptor (RyRs). Neurotransmitters such as acetylcholine 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 action potential 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 motion 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 troponin C or calmodulin as the cytosolic cells, however, involves a different tetrameric six-trans- calcium concentration decreases as a consequence, which membrane-span calcium channel: 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 nerves (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 muscle cell 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