Smooth muscle contraction is regulated by various mechanisms involving the release of calcium ions (Ca++) from the sarcoplasmic reticulum (SR) and the sarcolemma. These processes are responsible for the activation and subsequent regulation of intracellular Ca++ levels. The sarcolemma integrates multiple excitatory and inhibitory inputs to control the cellular response. Higher-order regulatory mechanisms can modify the activity of various pumps, exchangers, and enzymes. ATP hydrolysis is required for these processes. The refilling of the SR, known as store-operated Ca++ entry (SOCE), involves the interaction of a Ca++-sensitive protein called STIM on the SR and the sarcolemmal Ca++ channel Orai. Other important components include Ca++-calmodulin complex (CaCM), guanine nucleotide-binding proteins (G), inositol 1,4,5-trisphosphate (IP3), myosin light-chain kinase (MLCK), phosphatidylinositol bisphosphate (PIP2), and phospholipase C (PLC).

Inappropriate smooth muscle contraction is observed in various pathological situations. For instance, sustained vasospasm of a cerebral artery can occur several hours after a subarachnoid hemorrhage. It is believed that free radicals generated as a result of the hemorrhage increase intracellular Ca++ levels in the surrounding arterial smooth muscle cells. This rise in Ca++ activates MLCK, leading to cross-bridge phosphorylation and contraction. The resulting vasoconstriction reduces oxygen supply to other areas of the brain, potentially causing permanent injury or neuronal death. Vasodilators can be administered to restore blood flow, as the cerebral artery remains sensitive to vasoactive agents for a few days. During cerebral vasospasm, an increase in ROK activity and myosin light-chain phosphorylation has been observed. Administration of ROK inhibitors promotes relaxation of the vasospasm and reduces the level of myosin light-chain phosphorylation. However, smooth muscle cells eventually become unresponsive to vasodilators, losing contractile proteins and secreting extracellular collagen. Consequently, the artery remains constricted due to structural and mechanical changes that do not involve active contraction. The intracellular calcium levels in smooth muscle differ from skeletal muscle, where Ca++ release from the SR fully activates the contractile apparatus in response to action potentials.
•Fig. 14.10 Principalmechanismsdeterminingmyoplasmic[Ca++]insmoothmuscle.Releaseofcalciumfromthesarcoplasmicreticulum(SR)isarapidinitialeventinactivation,whereasboththeSRandthesarcolemmaparticipateinthesubsequentstimulus-dependentregulationofmyoplasmic[Ca++].Thesarcolemmaintegratesmanysimultaneousexcitatoryandinhibitoryinputstogovernthecellularresponse.Higher-orderregulatorymechanismscanaltertheactivityofvariouspumps,exchangers,orenzymes(theasterisk designateswell-establishedinstances).ThelabelATP indicatesthattheprocessrequiresATPhydrolysis;thequestion mark onthesarcolemmareferstotheCa++ pathwayimportantforrefillingtheSR(i.e.,store-operatedCa++ entry[SOCE]),whichappearstoinvolvetheinteractionofaCa++-sensitivestromalinteractionmolecule(STIM)ontheSRandthesarcolemmalCa++ channelOrai.CaCM,Ca++-calmodulincomplex;G,guaninenucleotide–bindingproteins;IP3,inositol1,4,5-trisphosphate;MLCK,myosinlight-chainkinase;PIP2,phosphatidylinositolbisphosphate;PLC,phospholipaseC.
Inappropriatecontractionofsmoothmuscleisassociatedwithmanypathologicalsituations.Oneexampleissustainedvasospasmofacerebralarterythatdevelopsseveralhoursafterasubarachnoidhemorrhage.Itisthoughtthatfreeradicalsgeneratedasaresultofthehemorrhageraisemyoplasmic[Ca++]insurroundingarterialsmoothmusclecells.Theriseinmyoplasmic[Ca++]activatesMLCK,whichleadstocross-bridgephosphorylationandcontraction.Thevasoconstrictiondeprivesotherareasofthebrainofoxygenandmayleadtopermanentinjuryordeathofsurroundingneurons.Forafewdaysthecerebralarteryremainssensitivetovasoactiveagents,andthereforetreatmentwithvasodilatorsmayrestoreflow.AnincreaseinROKactivityandMPphosphorylationhasbeenobservedduringcerebralvasospasm.AdministrationofROKinhibitorspromotesrelaxationofthevasospasmanddecreasesthelevelofmyosinlight-chainphosphorylation.Thesmoothmusclecellsceasetorespondtothevasodilatorsafterseveraldays,andtheylosecontractileproteinsandsecreteextracellularcollagen.Thelumenofthearteryremainsconstrictedasaresultofstructuralandmechanicalchangesthatdonotinvolveactivecontraction.
[Ca++] of smooth muscle. This differs from skeletal muscle, in which action potential–induced release of Ca++ from the SR fully activates the contractile apparatus.