Multi-tasking at the protein level: L-type calcium channels function as ionotropic and metabotropic activators of smooth muscle contraction

Ever since Sydney Ringer’s seminal observations in the late 1800’s describing the essential role of Ca2+ ions to support contraction in isolated frog hearts, a central focus in muscle physiology has been to understand the molecular mechanisms by which Ca2+ elicits muscle contraction, how it enters the myocyte and how it is handled by the cellular proteins and organelles. One of the main entry routes for extracellular Ca2+ into excitable tissues, such as muscle and nerve, is the voltage-gated Ca2+ channel, which resides in the plasma membrane and opens in response to depolarizing stimulus. Voltage-gated Ca2+ channels exist as a family comprised of three main subtypes denoted Cav1, 2 and 3; Cav1 is also commonly known as the L-type Ca2+ channel and is typically responsible for the dihydropyridine-sensitive Ca2+ influx that drives contraction in both striated and smooth muscles. Clinically, dihydropyridines may be used to lower blood pressure in hypertensive patients by reducing vascular smooth muscle tone and promoting vasodilation. In many smooth muscles, an acute depolarizing stimulus typically produces a biphasic contraction consisting of a rapid transient component and a more slowly developing sustained phase that is maintained in the presence of the depolarization. The sustained component of this contractile response is important physiologically, as smooth muscle cells in the gut and vascular wall are often required to constrict for prolonged periods. Extensive biochemical studies have demonstrated that the sustained phase of the contraction is supported by a process termed “calcium sensitization”, in which evoked biochemical modifications of key proteins permit the myofilaments to generate active force at substantially lower levels of cytosolic free Ca2+. Calcium sensitization is typically triggered by contractile agonists acting via seven transmembrane, G-protein-coupled receptors (e.g. a1-adrenergic and thromboxane GPCRs) and is supported by several signal transduction pathways in smooth muscle, with a major one involving the RhoA/Rho kinase phosphorylation cascade. By acting on key protein targets (i.e. the 20 kDa myosin light chain, the myosin phosphatase complex, CPI-17), this cascade ultimately results in elevated myosin ATPase activity, actin-myosin cross-bridge cycling and enhanced force generation at modest intracellular Ca2+ levels. Although previous studies had reported depolarization-induced smooth muscle contraction to be sensitive to inhibitors of the RhoA/Rho kinase signaling cascade, the important connection between membrane depolarization and the activation of this pathway has remained unclear. In the present study, the authors have examined the voltage-gated, L-type Ca2+ channel as the critical link between these two processes in smooth muscle. The results of their study indicate that in addition to its classic ionotropic role as a Ca2+ -selective, ionic pore at the plasma membrane, L-type channels may also act in a metabotropic fashion (i.e. similar to a GPCR) to stimulate a heterotrimeric G-protein(s), leading to activation of phospholipase C and inositol 1,4,5-trisphosphate (IP3) generation, along with activation of the RhoA/Rho kinase phosphorylation cascade. It thus appears that activation of the L-type Ca2+ channel may in turn stimulate two distinct, yet complementary signal transduction cascades, each of which supports a separate phase of the overall contractile response in smooth muscle.

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