The regulation of myoplasmic [Ca++] by smooth muscle SR is similar to that of skeletal muscle. The opening of SR Ca++ channels upon cellular stimulation leads to a rapid increase in myoplasmic [Ca++]. Unlike skeletal muscle, this release is not linked to voltage sensors but rather to the binding of the second messenger InsP3 to SR receptors. InsP3 is produced when a stimulus acts on sarcolemmal receptors coupled via a guanine nucleotide–binding protein (G protein) to activate phospholipase C (PLC). PLC breaks down the membrane phospholipid phosphatidylinositol bisphosphate (PIP2) into InsP3 and diacylglycerol. InsP3 then travels to the SR and opens the InsP3-gated Ca++ channel, causing the release of Ca++ from the SR into the myoplasm. This intricate process allows for graded release of Ca++ from the SR and enables various neurotransmitters and hormones to induce smooth muscle contraction. Calcium is reaccumulated in the SR through the activity of the SERCA, although extrusion of Ca++ from the smooth muscle cell also contributes to the decrease in myoplasmic [Ca++]. Refilling the SR with Ca++ involves not only reaccumulating cytosolic Ca++ but also relying on extracellular [Ca++]. The dependence on extracellular [Ca++] is believed to be due to the presence of a "store-operated" Ca++ channel located in the sarcolemma at junctional SR points. Several hormones and neurotransmitters can increase myoplasmic [Ca++] by stimulating InsP3 production. In vascular smooth muscle, for instance, sympathetic fibers of the autonomic nervous system innervate it. These fibers release norepinephrine as a neurotransmitter, which binds to α1-adrenergic receptors on vascular smooth muscle cells. This binding leads to G protein–dependent activation of PLC. PLC activation results in the production of InsP3, which then activates the InsP3-gated Ca++ channel in the SR, raising myoplasmic [Ca++] and causing vasoconstriction. Other agents that activate the InsP3 cascade and promote vasoconstriction include angiotensin II and vasopressin. Developing drugs that inhibit angiotensin II production (e.g., angiotensin-converting enzyme [ACE] inhibitors) can facilitate vasodilation, which is crucial for individuals with hypertension or congestive heart failure. As mentioned earlier, various agents can induce smooth muscle contraction without altering membrane potential (pharmacomechanical coupling). Activation of the InsP3 cascade by agonists serves as an example of pharmacomechanical coupling. Many hormones/agonists that activate PLC through G protein–coupled receptors also stimulate sarcolemmal Ca++ influx and activate RhoA/ROK. Consequently, intracellular [Ca++] increases, activating MLCK, while ROK activity inhibits MP. Both mechanisms work together to increase myosin light-chain phosphorylation.
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.