What Does Calcium Bind to in Smooth Muscle Contraction

Sheets or layers of smooth muscle cells are contained in the walls of diverse organs and tubes in the trunk, including the claret vessels, breadbasket, intestines, bladder, airways, uterus, and the penile and clitoral cavernosal sinuses. When made to contract, the smooth muscle cells shorten, thereby propelling the luminal contents of the organ, or the cell shortening varies the bore of a tube to regulate the flow of its contents. There are also bundles of smooth musculus cells attached to the hairs of the skin and to the iris and lens of the middle. When these bundles contract, the hairs become erect and the lens of the eye changes shape to focus lite on the retina.

Polish muscle cells lack the striated banding pattern found in cardiac and skeletal muscle, and they receive neural innervation from the autonomic nervous organization. In addition, the contractile state of smooth musculus is controlled by hormones, autocrine/paracrine agents, and other local chemical signals. Smooth musculus cells also develop tonic and phasic contractions in response to changes in load or length. Regardless of the stimulus, smooth muscle cells utilise cross-bridge cycling between actin and myosin to develop force, and calcium ions (Ca^two+) serve to initiate wrinkle.

This brief review will serve equally a refresher for those educators who teach in medical and graduate courses of physiology. Additionally, those professionals who are in need of an update on shine muscle physiology may detect this review to be useful. New concepts nigh regulatory mechanisms are presented to add depth to the understanding of the integrated responses of contraction and relaxation in smooth muscle. For those individuals desiring a more in-depth treatment of the subject, several recent reviews are recommended (1, 3, 5, vii, 9, 10, 18).

THE CONTRACTILE MECHANISM

In the intact body, the process of smooth muscle cell contraction is regulated principally by receptor and mechanical (stretch) activation of the contractile proteins myosin and actin. A modify in membrane potential, brought on past the firing of action potentials or past activation of stretch-dependent ion channels in the plasma membrane, tin can besides trigger contraction. For contraction to occur, myosin light chain kinase (MLC kinase) must phosphorylate the xx-kDa calorie-free chain of myosin, enabling the molecular interaction of myosin with actin. Energy released from ATP by myosin ATPase activity results in the cycling of the myosin cross-bridges with actin for contraction. Thus contractile activeness in smooth muscle is determined primarily by the phosphorylation state of the light concatenation of myosin—a highly regulated process. In some polish muscle cells, the phosphorylation of the lite chain of myosin is maintained at a depression level in the absence of external stimuli (i.e., no receptor or mechanical activation). This activity results in what is known as smooth muscle tone and its intensity can be varied.

Ca²⁺-DEPENDENT Wrinkle OF SMOOTH MUSCLE

Wrinkle of polish muscle is initiated by a Ca^two+-mediated change in the thick filaments, whereas in striated muscle Ca²⁺ mediates contraction by changes in the sparse filaments. In response to specific stimuli in smooth musculus, the intracellular concentration of Ca²⁺ increases, and this activator Ca²⁺ combines with the acidic protein calmodulin. This complex activates MLC kinase to phosphorylate the low-cal concatenation of myosin (Fig. i). Cytosolic Ca^two+ is increased through Ca^two+ release from intracellular stores (sarcoplasmic reticulum) too as entry from the extracellular space through Ca²⁺ channels (receptor-operated Ca^two+ channels). Agonists (norepinephrine, angiotensin II, endothelin, etc.) binding to serpentine receptors, coupled to a heterotrimeric One thousand protein, stimulate phospholipase C activity. This enzyme is specific for the membrane lipid phosphatidylinositol 4,5-bisphosphate to catalyze the formation of two strong second messengers: inositol trisphosphate (IP_iii) and diacylglycerol (DG). The binding of IP₃ to receptors on the sarcoplasmic reticulum results in the release of Ca²⁺ into the cytosol. DG, along with Ca²⁺, activates protein kinase C (PKC), which phosphorylates specific target proteins. There are several isozymes of PKC in shine muscle, and each has a tissue-specific part (due east.g., vascular, uterine, abdominal, etc.). In many cases, PKC has wrinkle-promoting furnishings such as phosphorylation of L-type Ca^two+ channels or other proteins that regulate cantankerous-bridge cycling. Phorbol esters, a group of synthetic compounds known to actuate PKC, mimic the action of DG and crusade contraction of smoothen muscle. Finally, L-type Ca²⁺ channels (voltage-operated Ca^two+ channels) in the membrane also open in response to membrane depolarization brought on by stretch of the shine muscle cell.

FIG. 1Regulation of polish musculus contraction. Diverse agonists (neurotransmitters, hormones, etc.) bind to specific receptors to actuate wrinkle in smooth muscle. Subsequent to this binding, the prototypical response of the jail cell is to increment phospholipase C action via coupling through a G protein. Phospholipase C produces 2 potent second messengers from the membrane lipid phosphatidylinositol 4,5-bisphosphate: diacylglycerol (DG) and inositol 1,4,five-trisphosphate (IP₃). IP_three binds to specific receptors on the sarcoplasmic reticulum, causing release of activator calcium (Ca²⁺). DG forth with Ca²⁺ activates PKC, which phosphorylates specific target proteins. In about smooth muscles, PKC has wrinkle-promoting effects such as phosphorylation of Ca²⁺ channels or other proteins that regulate cross-bridge cycling. Activator Ca²⁺ binds to calmodulin, leading to activation of myosin light chain kinase (MLC kinase). This kinase phosphorylates the light concatenation of myosin, and, in conjunction with actin, cross-bridge cycling occurs, initiating shortening of the smooth musculus prison cell. However, the summit in Caⁱⁱ⁺ concentration within the prison cell is transient, and the contractile response is maintained by a Ca^two+-sensitizing mechanism brought about by the inhibition of myosin phosphatase activity past Rho kinase. This Ca²⁺-sensitizing machinery is initiated at the same fourth dimension that phospholipase C is activated, and it involves the activation of the small GTP-binding protein RhoA. The precise nature of the activation of RhoA by the G protein-coupled receptor is not entirely clear but involves a guanine nucleotide commutation factor (RhoGEF) and migration of RhoA to the plasma membrane. Upon activation, RhoA increases Rho kinase activity, leading to inhibition of myosin phosphatase. This promotes the contractile state, since the light chain of myosin cannot be dephosphorylated.

Ca^two+ SENSITIZATION Mechanism AND CONTRACTION OF SMOOTH MUSCLE

In add-on to the Ca²⁺-dependent activation of MLC kinase, the state of myosin low-cal chain phosphorylation is further regulated by MLC phosphatase [aka myosin phosphatase (1, 4, 9, 11–sixteen)], which removes the high-free energy phosphate from the lite chain of myosin to promote smooth musculus relaxation (Fig. 1). There are 3 subunits of MLC phosphatase: a 37-kDa catalytic subunit, a 20-kDa variable subunit, and a 110- to 130-kDa myosin-binding subunit. The myosin-binding subunit, when phosphorylated, inhibits the enzymatic activity of MLC phosphatase, allowing the light chain of myosin to remain phosphorylated, thereby promoting contraction. The small Yard protein RhoA and its downstream target Rho kinase play an important role in the regulation of MLC phosphatase activeness. Rho kinase, a serine/threonine kinase, phosphorylates the myosin-binding subunit of MLC phosphatase, inhibiting its activeness and thus promoting the phosphorylated state of the myosin calorie-free chain (Fig. 1). Pharmacological inhibitors of Rho kinase, such every bit fasudil and Y-27632, block its activity by competing with the ATP-binding site on the enzyme. Rho kinase inhibition induces relaxation of isolated segments of smooth muscle contracted to many different agonists. In the intact beast, the pharmacological inhibitors of Rho kinase have been shown to cause relaxation of smooth musculus in arteries, resulting in a claret pressure-lowering effect (2, 17).

An of import question facing the smooth-muscle physiologist is: what is the link between receptor occupation and activation of the Ca²⁺-sensitizing action of the RhoA/Rho kinase-signaling cascade? Currently, it is thought that receptors activate a heterotrimeric K protein that is coupled to RhoA/Rho kinase signaling via guanine nucleotide substitution factors (RhoGEFs; Fig. i). Because RhoGEFs facilitate activation of RhoA, they regulate the duration and intensity of signaling via heterotrimeric Chiliad poly peptide receptor coupling. There are ∼70 RhoGEFs in the human genome, and three RhoGEFs accept been identified in smooth musculus: PDZ-RhoGEF, LARG (leukemia-associated RhoGEF), and p115-RhoGEF. Increased expression and/or activeness of RhoGEF proteins could augment contractile activation of smooth muscle and therefore play a role in diseases where an augmented response contributes to the pathophysiology (hypertension, asthma, etc.).

Several recent studies advise a role for additional regulators of MLC kinase and MLC phosphatase (13–16). Calmodulin-dependent protein kinase II promotes smooth muscle relaxation by decreasing the sensitivity of MLC kinase for Ca²⁺. Additionally, MLC phosphatase activity is stimulated by the 16-kDa poly peptide telokin in phasic polish muscle and is inhibited by a downstream mediator of DG/protein kinase C, CPI-17.

SMOOTH Musculus RELAXATION

Smoothen muscle relaxation occurs either as a result of removal of the contractile stimulus or by the directly action of a substance that stimulates inhibition of the contractile mechanism (e.g., atrial natriuretic factor is a vasodilator). Regardless, the process of relaxation requires a decreased intracellular Ca²⁺ concentration and increased MLC phosphatase activity (Fig. 2) (x, 16). The mechanisms that sequester or remove intracellular Ca^two+ and/or increase MLC phosphatase activity may become altered, contributing to abnormal shine muscle responsiveness.

FIG. 2Relaxation of smooth muscle. Smooth muscle relaxation occurs either as a issue of removal of the contractile stimulus or by the direct action of a substance that stimulates inhibition of the contractile mechanism. Regardless, the procedure of relaxation requires a decreased intracellular Ca²⁺ concentration and increased MLC phosphatase activeness. The sarcoplasmic reticulum and the plasma membrane contain Ca,Mg-ATPases that remove Ca²⁺ from the cytosol. Na⁺/Ca²⁺ exchangers are also located on the plasma membrane and aid in decreasing intracellular Caⁱⁱ⁺. During relaxation, receptor- and voltage-operated Ca²⁺ channels in the plasma membrane close resulting in a reduced Ca²⁺ entry into the cell.

A subtract in the intracellular concentration of activator Ca²⁺ elicits smoothen muscle cell relaxation. Several mechanisms are implicated in the removal of cytosolic Ca²⁺ and involve the sarcoplasmic reticulum and the plasma membrane. Ca^two+ uptake into the sarcoplasmic reticulum is dependent on ATP hydrolysis. This sarcoplasmic reticular Ca,Mg-ATPase, when phosphorylated, binds two Caⁱⁱ⁺ ions, which are then translocated to the luminal side of the sarcoplasmic reticulum and released. Mg^two+ is necessary for the activity of the enzyme; it binds to the catalytic site of the ATPase to mediate the reaction. The sarcoplasmic reticular Ca,Mg-ATPase is inhibited by several unlike pharmacological agents: vanadate, thapsigargin, and cyclopiazonic acid. Sarcoplasmic reticular Ca²⁺-bounden proteins also contribute to decreased intracellular Ca²⁺ levels. Recent studies have identified calsequestrin and calreticulin as sarcoplasmic reticular Ca²⁺-binding proteins in smooth muscle.

The plasma membrane also contains Ca,Mg-ATPases, providing an additional mechanism for reducing the concentration of activator Ca²⁺ in the cell. This enzyme differs from the sarcoplasmic reticular poly peptide in that it has an autoinhibitory domain that tin can exist bound by calmodulin, causing stimulation of the plasma membrane Ca²⁺ pump.

Na⁺/Caⁱⁱ⁺ exchangers are also located on the plasma membrane and help in decreasing intracellular Ca²⁺. This depression-affinity antiporter is closely coupled to intracellular Ca²⁺ levels and can exist inhibited by amiloride and quinidine.

Receptor-operated and voltage-operated Ca^two+ channels located in the plasma membrane are important in Ca^two+ influx and smooth muscle wrinkle, equally previously mentioned. Inhibition of these channels can elicit relaxation. Channel antagonists such every bit dihydropyridine, phenylalkylamines, and benzothiazepines demark to distinct receptors on the channel protein and inhibit Ca^two+ entry in smooth musculus.

ABNORMAL CONTRACTILE REGULATION OF SMOOTH MUSCLE

Alterations in the regulatory processes maintaining intracellular Ca²⁺ and MLC phosphorylation accept been proposed as possible sites contributing to the aberrant contractile events in smooth muscle cells of various organs and tissues (2, 5, 8, 9). In addition, alterations in upstream targets that affect Ca²⁺ and MLC phosphorylation have as well been implicated. For example, changes in the affinity, number, or subtype of α-adrenergic receptors leading to enhanced vasoconstriction have been characterized in arterial shine musculus cells in some types of hypertension. Increases in the action of RhoA/Rho kinase signaling lead to increased contractile responses that may contribute to erectile dysfunction in the penis and clitoris. Increased activity of the RhoA/Rho kinase-signaling pathway may also contribute to augmented wrinkle or spastic beliefs of polish musculus in disease states such as asthma or atherosclerosis.

Impaired function may occur as the issue of a change in the straight activity of a substance that stimulates inhibition of the contractile mechanism. For example, decreased relaxation responses can be due to a reduction in cyclic nucleotide-dependent signaling pathways coupled with reductions in receptor activation (β-adrenergic receptors and cyclic AMP) or agonist bioavailability (endothelium dysfunction, reduced nitric oxide and cyclic GMP). Importantly, it is the complexity and redundancy of these jail cell signaling pathways regulating intracellular Ca²⁺ and MLC phosphorylation in smooth muscle that provide therapeutic potential for dysfunction.

SUMMARY

Polish musculus derives its name from the fact that it lacks the striations characteristic of cardiac and skeletal musculus. Layers of smooth muscle cells line the walls of diverse organs and tubes, and the contractile function of shine muscle is non under voluntary command. Contractile activity in smooth muscle is initiated by a Ca²⁺-calmodulin interaction to stimulate phosphorylation of the light concatenation of myosin. A Ca²⁺ sensitization of the contractile proteins is signaled by the RhoA/Rho kinase pathway to inhibit the dephosphorylation of the light chain by myosin phosphatase, maintaining force generation. Removal of Ca²⁺ from the cytosol and stimulation of myosin phosphatase initiate the procedure of smooth muscle relaxation.

This work was supported by grants from the National Heart, Lung, and Claret Institute (HL-18575 and HL-71138).

Address for reprint requests and other correspondence: R. C. Webb, Dept. of Physiology, Medical College of Georgia, 1120 Fifteenth St., Augusta, GA 30912–3000 (Eastward-post: [email protected]).

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Source: https://journals.physiology.org/doi/10.1152/advan.00025.2003

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