Abstract
TRPC channels are a family of nonselective cation channels that regulate ion homeostasis and intracellular Ca2+ 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 IC50s 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 IC50s 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.
Highlights
Transient receptor potential canonical (TRPC) channels belong to the TRP cation channel superfamily
These experiments confirmed that 10 mM norgestimate almost completely inhibited TRPC3 and 26 (Figure 2A–C)
Our search for new pharmacological TRPC channel modulators led to the discovery of two steroids, namely norgestimate and progesterone, which differentially inhibited TRPC-mediated currents and Ca2+ influx
Summary
Transient receptor potential canonical (TRPC) channels belong to the TRP cation channel superfamily. Seven TRPC channels, TRPC1–7, have been found in rodents. They all conduct Ca2+ in addition to monovalent cations and can be activated via membrane receptors linked to phospholipase C signaling. Downstream of phospholipase C the activation mechanisms of TRPC channels are not well defined but one subclass, namely TRPC3, 26 and 27, as well as the structurally more distinct TRPC2 respond to the phospholipase C hydrolysis product diacylglycerol. The remaining family members, are diacylglycerol-insensitive (reviewed in [1,2,3]). Genetic models have been instrumental in defining the physiological roles of TRPC channels. The involvement of TRPC4 and TRPC6 in vasoregulation [4,5], TRPC1 in muscle function [6,7], TRPC2 in pheromone signaling [8,9], TRPC3 in motor coordination [10,11], and most recently of TRPC5 [12] in innate fear responses has been elucidated using knockout mice
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