Unraveling Smooth Muscle Contraction: The TRP Link

Molecular mechanisms associated with activation of mI_CAT and smooth muscle contraction. Activation of M2 and M3 muscarinic receptors is coupled to signal transduction events via G_i/o and G_q/ll pathways leading to activation of adenylyl cyclase (AC) and PLC. These events result in generation of intracellular messengers cyclic AMP (not indicated in figure) and DAG as well as [Ca²⁺]_i increase owing to IP₃-mediated Ca²⁺ release via the inositol trisphosphate receptor (IP₃R). TRPC4 and TRPC6 channels are activated as a consequence. TRPC6 is primarily activated by DAG, whereas the activation of TRPC4 depends on G_i/0 and the channel is also subject to modulation by PIP₂ as well as [Ca²⁺]_i. The channels allow influx of Na⁺ and Ca²⁺, resulting in depolarization of the cells that in turn leads to activation of voltage-dependent calcium channels (VDCC), which provide the bulk of the Ca²⁺ required for contraction. Thus, these initial signaling events are the key determinants of intestinal motility.