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

Abstract

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. 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. 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. 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. 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.

Fig. 1

Receptor-induced TRPC6 activation via diacylglycerol (DAG) results in Na⁺ entry, membrane depolarization and activation of Ca²⁺ entry though L-type voltage-activated Ca²⁺ channels. GPCR, G-Protein-coupled receptor; PLC, phospholipase C; PIP₂, phosphatidylinositol 4,5-bisphosphate; IP₃, inositol 1,4,5-trisphosphate.

Fig. 2

TRPC6 channels are sensors of membrane stretch. Channel opening allows Na⁺ entry, smooth muscle cell depolarization and the activation of activation of L-type voltage-activated Ca²⁺ channels. Such coupling between stretch and activation of Ca²⁺ entry signals may be crucial in mediating the myogenic tone response of vascular smooth muscle.

Fig. 3

Scheme showing coupling between endoplasmic reticulum (ER) stores and Ca²⁺ entry mechanisms mediated by receptor-induced signalling pathways in smooth muscle and other cell types. G-Protein-coupled receptors (GPCR) or tyrosine kinase-coupled receptors (TKR) activated by agonists (A) are shown to activate either phospholipase C (PLC)-β or PLC-γ and the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP₂) to release the head group inositol 1,4,5-trisphophate (IP₃) into the cytosol. Inositol 1,4,5-trisphophate receptors (IP₃R) on the ER membrane are activated to release Ca²⁺ from stores. The lowered luminal Ca²⁺ causes dissociation of Ca²⁺ bound to the low-affinity EF-hand Ca²⁺-binding site on the N-terminus of stromal-interacting molecule (STIM) 1. This Ca²⁺ dissociation causes STIM1 molecules to aggregate and be translocated to regions of the ER in close proximity to the plasma membrane (PM) and to interact directly with the Orai1 protein in the PM, which is the highly Ca²⁺-selective store-operated channel moiety.