STIM, ORAI and TRPC channels in the control of calcium entry signals in smooth muscle

1. Ca²⁺ entry signals are crucial in the control of smooth muscle contraction. Smooth muscle cells are unusual in containing plasma membrane (PM) Ca²⁺ entry channels that respond to voltage changes, receptor activation and Ca²⁺ store depletion. 2. Activation of these channel subtypes is highly coordinated. The TRPC6 channel, widely expressed in most smooth muscle cell types, is largely non-selective to cations and is activated by diacylglycerol arising from receptor-induced phosholipase C activation. 3. Receptor activation results largely in Na⁺ ion movement through TRPC6 channels, depolarization and subsequent activation of voltage-dependent L-type Ca²⁺ channels. The TRPC6 channels also appear to be activated by mechanical stretch, resulting again in depolarization and L-type Ca²⁺ channel activation. Such a coupling may be crucial in mediating the myogenic tone response in vascular smooth muscle. 4. The emptying of stores mediated by inositol 1,4,5-trisphosphate receptors triggers the endoplasmic reticulum (ER) Ca²⁺ sensing protein stromal-interacting molecule (STIM) 1 to translocate into defined ER-PM junctional areas in which coupling occurs to Orai proteins, which serve as highly Ca²⁺- selective low-conductance Ca²⁺ entry channels. 5. These ER-PM junctional domains may serve as crucial sites of interaction and integration between the function of store-operated, receptor-operated and voltage-operated Ca²⁺ channels. The STIM, Orai and TRPC channels represent highly promising new pharmacological targets through which such control may be induced.