TRPM4 Is a Ca2+-Activated Nonselective Cation Channel Mediating Cell Membrane Depolarization

Abstract

Calcium-activated nonselective (CAN) cation channels are expressed in various excitable and nonexcitable cells supporting important cellular responses such as neuronal bursting activity, fluid secretion, and cardiac rhythmicity. We have cloned and characterized a second form of TRPM4, TRPM4b, a member of the TRP channel family, as a molecular candidate of a CAN channel. TRPM4b encodes a cation channel of 25 pS unitary conductance that is directly activated by [Ca2+]i with an apparent K(D) of approximately 400 nM. It conducts monovalent cations such as Na+ and K+ without significant permeation of Ca2+. TRPM4b is activated following receptor-mediated Ca2+ mobilization, representing a regulatory mechanism that controls the magnitude of Ca2+ influx by modulating the membrane potential and, with it, the driving force for Ca2+ entry through other Ca2+-permeable pathways.

Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

“…In the Gon-2 (dx22) allele, a conserved G427 is affected, which corresponds to G144 in TRPM6 and is located close to the critical S141 mutated in an HSH patient. In aggregate, experiments with TRPM6(S141L) strengthen the notion of a crucial role of the conserved N-terminal region for TRPM function as proposed for Gon-2 (West et al 2001), TRPM1 (Xu et al 2001), TRPM2 (Zhang et al 2003a) and TRPM4A/ TRPM4B isoforms (Launay et al 2002;Xu et al 2001).…”

“…TRPM3 appears to be activated by hypoosmotic cell swelling, rises of intracellular Ca 2+ and by D-erythro-sphingosine (Grimm et al 2003(Grimm et al , 2004Lee et al 2003). Two other TRPM subfamily members, TRPM4 and TRPM5, are mainly permeable for monovalent cations, gated by increases in intracellular Ca 2+ and exhibit a pronounced voltage modulation (Hofmann et al 2003;Launay et al 2002;Liu and Liman, 2003;Nilius et al 2003;Prawitt et al 2003). Intriguingly, mice with a genetically disrupted TRPM5 gene display impaired sweet, bitter and umami taste perception (Zhang et al 2003b), but the precise role of TRPM5 in taste receptor cells is still under debate (Hofmann et al 2003;Perez et al 2002;Prawitt et al 2003;Zhang et al 2003b).…”

Structures of the calcium-activated, non-selective cation channel TRPM4

“…7 ). While TRPM4 is ubiquitously expressed in pancreas, heart, prostate, renal tubule and many other tissues and organs 9,10 , TRPM5 is mainly detected in taste receptor cells 11 .…”

Calcium sensitive non-selective cation current promotes seizure-like discharges and spreading depression in a model neuron

“…4). Incidentally, the Hill coefficient of the [Ca 2+ ] i -activated NSCC generated by TRPM4b channels was either 4 or 6 depending on the treatment of the preparation (Launay et al 2002).…”

“…(Caeser et al 1993;Crepel et al 1994) and substantia nigra inhibitory neurons (Lee and Tepper 2007). The TRPM4b channel, which is expressed in mammalian neurons, has been characterized as a [Ca 2+ ] i -activated, Ca 2+ -impermeable, monovalent cation-permeable channel (Fleig and Penner 2004;Launay et al 2002). Since uptake of Ca 2+ into neurons results simultaneously in an increase in [Ca 2+ ] i and a decrease in [Ca 2+ ] o , if the two Ca 2+ sensitive currents co-exist in the same cell, they are expected to reinforce one another and in fact could perhaps be generated by the same channel (see Section 3).…”