Excitationcontraction Coupling

The physiological processes that begin with cardiac sar-colemmal membrane depolarization and culminate in contraction are collectively defined as myocardial excitation-contraction coupling. Depolarization of the cardiac myocyte sarcolemmal membrane during the action potential results in the intracellular entry of extracellular calcium. The major regulators of the transsarcolem-mal entry of calcium include L-type calcium channels and autonomic receptors (Fig. 15.1). These membrane-bound proteins all contribute to the influx of a minute quantity of calcium from outside the cell into the myocyte. The entry of this small quantity of calcium causes the release of the large reservoir of calcium stored in the sarcoplasmic reticulum (SR) through the SR calcium release channel (ryanodine receptor). This large reservoir of calcium interacts with tropomyosin to allow the actin and myosin filaments to overlap, resulting in systolic myocardial contraction. Diastolic relaxation results from the resequestration of this large reservoir of calcium back into the sarcoplasmic reticulum through the SR calcium adenosine triphosphatase (ATPase). Calcium exits the cell through the Na+-Ca++ exchanger and sarcolemmal Ca++ATPase.

Autonomic receptors further regulate calcium influx through the sarcolemma (Fig. 15.1). p-Adrenergic stimulation results in the association of a catalytic subunit of a G protein coupled to the p-receptor. This stimulates the enzyme adenylyl cyclase to convert ATP to cyclic adenosine monophosphate (cAMP). Increasing cAMP production results in a cAMP-dependent phosphoryla-tion of the L-type calcium channel and a subsequent increase in the probability of the open state of the channel. This translates to an increase in transsarcolemmal calcium influx during phase 2 (the plateau phase) of the cardiac muscle action potential. The effects of transient increases in intracellular levels of cAMP are tightly con trolled by phosphodiesterases and phosphatases that prevent indefinite phosphorylation and activation of regulatory proteins. a-Adrenoceptor stimulation results in the phospholipase C-mediated breakdown of phos-phatidylcholine to inositol triphosphate and diacyl glyc-erol; these second messengers further enhance mobilization of both transsarcolemmal calcium influx and SR calcium efflux.

Binding of angiotensin II to its cardiac myocyte receptor acutely increases Ca++ influx through sarcolem-mal L-type calcium channels. The long-term effects of chronic angiotensin II receptor stimulation include cardiac myocyte hypertrophy through enhanced expression of growth factor genes.

The maintenance of a resting membrane potential in cardiac myocytes, as well as all cells, depends on metabolic energy (ATP) that is used by the Na+-K+ ATPase to drive the gradients for Na+ and K+ between the in-tracellular and extracellular spaces. Cardiac glycosides are known to bind to this protein.

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