Deletion of TRPC4 and TRPC6 in Mice Impairs Smooth Muscle Contraction and Intestinal Motility In Vivo

Background & AimsDownstream effects of muscarinic receptor stimulation in intestinal smooth muscle include contraction and intestinal transit. We thought to determine whether classic transient receptor potential (TRPC) channels integrate the intracellular signaling cascades evoked by the stimulated receptors and thereby contribute to the control of the membrane potential, Ca-influx, and cell responses.MethodsWe created trpc4-, trpc6-, and trpc4/trpc6-gene–deficient mice and analyzed them for intestinal smooth muscle function in vitro and in vivo.ResultsIn intestinal smooth muscle cells TRPC4 forms a 55 pS cation channel and underlies more than 80% of the muscarinic receptor-induced cation current (mICAT). The residual mICAT depends on the expression of TRPC6, indicating that TRPC6 and TRPC4 determine mICAT channel activity independent of other channel subunits. In TRPC4-deficient ileal myocytes the carbachol-induced membrane depolarizations are diminished greatly and the atropine-sensitive contraction elicited by acetylcholine release from excitatory motor neurons is reduced greatly. Additional deletion of TRPC6 aggravates these effects. Intestinal transit is slowed down in mice lacking TRPC4 and TRPC6.ConclusionsIn intestinal smooth muscle cells TRPC4 and TRPC6 channels are gated by muscarinic receptors and are responsible for mICAT. They couple muscarinic receptors to depolarization of intestinal smooth muscle cells and voltage-activated Ca2+-influx and contraction, and thereby accelerate small intestinal motility in vivo.