Mechanism of Calcium Activation in Vascular Smooth Muscle

The primary stimulus for activation of vascular smooth muscle is an increase in the cytosolic free Ca2+ concentration. The level of activating Ca2+ is determined by a variety of Ca2+ homeostatic mechanisms. Ca2+ entry from the extracellular space occurs through the resting Ca2+ leak and the excitable Ca2+ channels: viz. voltage-gated, receptor-operated and stretch-activated channels. Ca2+ release from sarcoplasmic reticulum is induced by inositol triphosphate (IP3) and, possibly, by Ca2+ itself. Activating Ca2+ binds to calmodulin, forming a complex which induces myosin light chain phosphorylation and initiates smooth muscle contraction. The continuous Ca2+ entry together with the higher Ca2+ sensitivity of the contractile apparatus can then maintain smooth muscle tension. Ca2+ buffering by the sarcoplasmic reticulum and Ca2+ extrusion by Ca2+ pumps serve to lower the cytosolic free Ca2+ concentration. These Ca2+-lowering mechanisms are possibly regulated by cyclic nucleotides.