Tsvilovskyy VV, Zholos AV, Aberle T, Philipp SE, Dietrich A, Zhu MX, Birnbaumer L, Freichel M, Flockerzi V
Deletion of TRPC4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo. [JOURNAL ARTICLE]
Gastroenterology 2009 Jun 21.
BACKGROUND & AIMS:: Downstream effects of muscarinic receptor stimulation in intestinal smooth muscle include contraction and intestinal transit. We thought to determine whether classical 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.
METHODS:: We created trpc4-, trpc6- and trpc4/trpc6-gene deficient mice and analyzed them for intestinal smooth muscle function in vitro and in vivo.
RESULTS:: In intestinal smooth muscle cells TRPC4 forms a 55 pS cation channel and underlies >80% of the muscarinic receptor-induced cation current or mI(CAT). The residual mI(CAT) depends on the expression of TRPC6 indicating that TRPC6 and TRPC4 determine mI(CAT) channel activity independent of other channel subunits. In TRPC4-deficient ileal mocytes the carbachol-induced membrane depolarizations are greatly diminished and the atropine sensitive contraction elicited by acetylcholine release from excitatory motor neurons is greatly reduced. Additional deletion of TRPC6 aggravates these effects. Intestinal transit is slowed down in mice lacking TRPC4 and TRPC6.
CONCLUSIONS:: In intestinal smooth muscle cells TRPC4 and TRPC6 channels are gated by muscarinic receptors and are responsible for mI(CAT). They couple muscarinic receptors to depolarization of intestinal smooth muscle cells, voltage-activated Ca(2+)-influx and contraction and thereby accelerate small intestinal motility in vivo.
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