The role of smooth muscle SR in regulating myoplasmic [Ca++] is comparable to that of skeletal muscle. Stimulation of the cell opens SR Ca++ channels, and myoplasmic [Ca++] increases rapidly. This release is not linked to voltage sensors, as is the case in skeletal muscle, but to binding of the second messenger InsP3 to receptors in the SR. InsP3 is generated by a stimulus that acts on sarcolemmal receptors that are coupled via a guanine nucleotide–binding protein (G protein) to activate phospholipase C (PLC) (see ). PLC hydrolyzes the membrane phospholipid phosphatidylinositol bisphosphate (PIP2) into InsP3 and diacylglycerol. InsP3 then diffuses to the SR and opens the InsP3-gated Ca++ channel, thereby resulting in release of Ca++ from the SR into the myoplasm. This complex process may permit graded release of Ca++ from the SR and also enable many different neurotransmitters and hormones to effect smooth muscle contraction. Calcium is reaccumulated by the SR through the activity of the SERCA, although as indicated later, extrusion of Ca++ from the smooth muscle cell also contributes to the reduction in myoplasmic [Ca++]. Refilling of the SR with Ca++ not only involves reaccumulation of cytosolic Ca++ but also depends on the extracellular [Ca++]. The dependence on extracellular [Ca++] is thought to reflect the operation of a “store-operated” Ca++ channel present in the sarcolemma at points near underlying SR called junctional SR.
A variety of hormones and neurotransmitters elevate myoplasmic [Ca++] by stimulating InsP3 production. Vascular smooth muscle, for example, is innervated by sympathetic fibers of the autonomic nervous system. These fibers use norepinephrine as a neurotransmitter, which when released binds to α1-adrenergic receptors on vascular smooth muscle cells and results in G protein–dependent activation of PLC. Activation of PLC results in production of InsP3, which activates the InsP3-gated Ca++ channel in the SR, thereby elevating myoplasmic [Ca++] and causing vasoconstriction. Other agents that promote vasoconstriction by activating the InsP3 cascade include angiotensin II and vasopressin. Development of drugs that block production of angiotensin II (e.g., angiotensin-converting enzyme [ACE] inhibitors) provides a means of promoting vasodilation that is important for individuals with hypertension or congestive heart failure. As mentioned previously, a variety of agents can produce contraction of smooth muscle without altering membrane potential (i.e., pharmacomechanical coupling). Agonist-induced activation of the InsP3 cascade represents an example of pharmacomechanical coupling. Many of the hormones/agonists that activate PLC through G protein– coupled receptors also promote sarcolemmal Ca++ influx and activation of RhoA/ROK. The net effect is a rise in intracellular [Ca++], which activates MLCK, concomitant with a rise in ROK activity, which inhibits MP, both of which act complementarily to increase the level myosin light-chain phosphorylation.