Receptor-mediated Regulation of the Nonselective Cation Channels TRPC4 and TRPC5

Abstract

Mammalian transient receptor potential channels (TRPCs) form a family of Ca2؉ -permeable cation channels currently consisting of seven members, TRPC1-TRPC7. These channels have been proposed to be molecular correlates for capacitative Ca 2؉ entry channels. There are only a few studies on the regulation and properties of the subfamily consisting of TRPC4 and TRPC5, and there are contradictory reports concerning the possible role of intracellular Ca 2؉ store depletion in channel activation. We therefore investigated the regulatory and biophysical properties of murine TRPC4 and TRPC5 (mTRPC4/5) heterologously expressed in human embryonic kidney cells. Activation of G q/11 -coupled receptors or receptor tyrosine kinases induced Mn 2؉ entry in fura-2-loaded mTRPC4/5-expressing cells. Accordingly, in whole-cell recordings, stimulation of G q/11 -coupled receptors evoked large, nonselective cation currents, an effect mimicked by infusion of guanosine 5-3-O-(thio)triphosphate (GTP␥S). However, depletion of intracellular Ca2؉ stores failed to activate mTRPC4/5. In inside-out patches, single channels with conductances of 42 and 66 picosiemens at ؊60 mV for mTRPC4 and mTRPC5, respectively, were stimulated by GTP␥S in a membrane-confined manner. Thus, mTRPC4 and mTRPC5 form nonselective cation channels that integrate signaling pathways from G-protein-coupled receptors and receptor tyrosine kinases independently of store depletion. Furthermore, the biophysical properties of mTRPC4/5 are inconsistent with those of I CRAC , the most extensively characterized store-operated current.

Intrinsic light responses of retinal ganglion cells projecting to the circadian system

“…Clapham et al, 2001;Minke & Cook, 2002). Specifically, the I-V characteristics closely resemble those reported for the TRPC6 channel in A7r5 smooth muscle cells (Jung et al, 2002), the mTRP6 channel in vascular smooth muscle (Inoue et al, 2001), and the TRPC4 and TRPC5 channels expressed in embryonic kidney cells (Shaefer et al, 2000). Furthermore, the I-V characteristics and amplitude of the light-activated current at −60 mV were largely unaffected by total replacement of extracellular Na + with choline.…”

Mechanisms of leukotriene D4‐induced constriction in human small bronchioles

“…Speci®cally, TRP4 channels have been suggested as a part of a native Ca 2+ release activated channels in adrenal cells (Philipp et al, 2000). However, Schaefer et al, (2000) have reported that the properties of murine TRP4 suit this role considerably less well than reported for its bovine counterpart, and in vascular smooth muscle TRP1 has been suggested to ful®l a similar role (Xu & Beech, 2001). While the e ect of CPA shows that SOC may well be present in human small bronchioles, the lack of any signi®cant e ect of low micromolar concentrations of trivalent cations or 2-APB on the LTD 4 -induced bronchoconstriction, both of which are reported to block SOC, tends to suggest that SOC is not the major Ca 2+ entry pathway during LTD 4 stimulation of human small bronchioles.…”

Increased inwardly rectifying potassium currents in HEK-293 cells expressing murine transient receptor potential 4

“…While two groups have demonstrated TG-stimulated Trp4 activity [8,18,20], another group showed that the channel only responded to receptor agonist but not store-depletion by TG [21]. Using Trp4-specific antibodies, we showed that mTrp4 was expressed and was localized at or near plasma membrane of the transfected HEK 293 cells.…”

“…was challenged by a recent study that showed that murine Trp4 (mTrp4), as well as the closely related Trp5, did not respond to store depletion, but rather to the activation of phospholipase C by cell-surface receptors [21]. In addition, the study also suggested that mTrp4 and mTrp5 form non-selective cation channels instead of Ca# + -selective channels, when expressed in HEK-293 cells.…”