title: Inhibition of diacylglycerol-sensitive TRPC channels by synthetic and natural steroids.
abstract: TRPC channels are a family of nonselective cation channels that regulate ion homeostasis and intracellular Ca(2+) signaling in numerous cell types. Important physiological functions such as vasoregulation, neuronal growth, and pheromone recognition have been assigned to this class of ion channels. Despite their physiological relevance, few selective pharmacological tools are available to study TRPC channel function. We, therefore, screened a selection of pharmacologically active compounds for TRPC modulating activity. We found that the synthetic gestagen norgestimate inhibited diacylglycerol-sensitive TRPC3 and TRPC6 with IC(50)s of 3-5 µM, while half-maximal inhibition of TRPC5 required significantly higher compound concentrations (>10 µM). Norgestimate blocked TRPC-mediated vasopressin-induced cation currents in A7r5 smooth muscle cells and caused vasorelaxation of isolated rat aorta, indicating that norgestimate could be an interesting tool for the investigation of TRP channel function in native cells and tissues. The steroid hormone progesterone, which is structurally related to norgestimate, also inhibited TRPC channel activity with IC(50)s ranging from 6 to 18 µM but showed little subtype selectivity. Thus, TRPC channel inhibition by high gestational levels of progesterone may contribute to the physiological decrease of uterine contractility and immunosuppression during pregnancy.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Miehe
authors.forename: Peter
authors.initials: P
authors.lastname: Crause
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Matthias
authors.initials: M
authors.lastname: Löhn
authors.forename: Heinz-Werner
authors.initials: HW
authors.lastname: Kleemann
authors.forename: Thomas
authors.initials: T
authors.lastname: Licher
authors.forename: Werner
authors.initials: W
authors.lastname: Dittrich
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rütten
authors.forename: Carsten
authors.initials: C
authors.lastname: Strübing
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism*; D006801:Humans; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009644:Norgestrel / Q000031:analogs & derivatives / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000378:metabolism; D013256:Steroids / Q000138:chemical synthesis / Q000494:pharmacology*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000074287:TRPC6 Cation Channel; D014667:Vasopressins / Q000494:pharmacology
chemical_list: D004075:Diglycerides; D017483:Receptors, Vasopressin; D013256:Steroids; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human; D014667:Vasopressins; D009644:Norgestrel; D011374:Progesterone; C017576:norgestimate; D002118:Calcium