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

Local calcium transients ('Ca²⁺ sparks') are thought to be elementary Ca²⁺ signals in heart, skeletal and smooth muscle cells. Ca²⁺ 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, Ca²⁺ 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 [Ca²⁺](i) and contraction ('myogenic tone') of arteries. Ca²⁺ 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 Ca²⁺ sparks by ryanodine, or of K(Ca) channels by iberiotoxin, leads to membrane depolarization, activation of L-type voltage-gated Ca²⁺ channels, and vasoconstriction. Conversely, activation of Ca²⁺ sparks can lead to vasodilation through activation of K(Ca) channels. Our recent work is aimed at studying the properties and roles of Ca²⁺ sparks in the regulation of arterial smooth muscle function. The modulation of Ca²⁺ spark frequency and amplitude by membrane potential, cyclic nucleotides and protein kinase C will be explored. The role of local Ca²⁺ entry through voltage-dependent Ca²⁺ channels in the regulation of Ca²⁺ spark properties will also be examined. Finally, using functional evidence from cardiac myocytes, and histological evidence from smooth muscle, we shall explore whether Ca²⁺ channels, RyR channels, and K(Ca) channels function as a coupled unit, through Ca²⁺ acid voltage, to regulate arterial smooth muscle membrane potential and vascular tone.