Ca2+ channels, ryanodine receptors and Ca2+‐activated K+ channels: a functional unit for regulating arterial tone

Abstract

Local calcium transients (‘Ca 2+ sparks’) are thought to be elementary Ca 2+ signals in heart, skeletal and smooth muscle cells. Ca 2+ sparks result from the opening of a single, or the coordinated opening of many, tightly clustered ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR). In arterial smooth muscle, Ca 2+ sparks appear to be involved in opposing the tonic contraction of the blood vessel. Intravascular pressure causes a graded membrane potential depolarization to approximately −40 mV, an elevation of arterial wall [Ca 2+]i and contraction (‘myogenic tone’) of arteries. Ca 2+ sparks activate calcium‐sensitive K+ (K Ca) channels in the sarcolemmal membrane to cause membrane hyperpolarization, which opposes the pressure induced depolarization. Thus, inhibition of Ca 2+ sparks by ryanodine, or of K Ca channels by iberiotoxin, leads to membrane depolarization, activation of L‐type voltage‐gated Ca 2+ channels, and vasoconstriction. Conversely, activation of Ca 2+ sparks can lead to vasodilation through activation of K Ca channels. Our recent work is aimed at studying the properties and roles of Ca 2+ sparks in the regulation of arterial smooth muscle function. The modulation of Ca 2+ spark frequency and amplitude by membrane potential, cyclic nucleotides and protein kinase C will be explored. The role of local Ca 2+ entry through voltage‐dependent Ca 2+ channels in the regulation of Ca 2+ spark properties will also be examined. Finally, using functional evidence from cardiac myocytes, and histological evidence from smooth muscle, we shall explore whether Ca 2+ channels, RyR channels, and K Ca channels function as a coupled unit, through Ca 2+ and voltage, to regulate arterial smooth muscle membrane potential and vascular tone.