Isoform- and receptor-specific channel property of canonical transient receptor potential (TRPC)1/4 channels

Abstract

Transient receptor potential canonical (TRPC) 1, the first mammalian homologue of Drosophila trp gene, is distributed widely in mammalian cells and is involved in many physiological functions. TRPC1 is reported to be functional following heteromeric formation with other TRPC channels such as TRPC4 or TRPC5. It is known that the composition of this widely distributed TRPC1 is far from simple; functionality of such channels has been highly controversial. Furthermore, TRPC1 gene is known to have two splicing variants; one encodes long (TRPC1α) and the other encodes short (TRPC1β) TRPC1 isoforms, respectively. In this study, we examined the functionality of TRPC1/4 channels using various activation systems. Gq/11-coupled receptor (e.g., M1 or M3 receptors) stimulation significantly increased TRPC1α/4 currents but induced mild activation of TRPC1β/4. In addition, when expressed with TRPC4, TRPC1α acted as a pore-constituting subunit and not a β ancillary subunit. Multimerized with TRPC4, TRPC1α also generated strong pore field strength. We also found that Gi/o-coupled receptor (e.g., M2 receptor) stimulation was insufficient to activate TRPC1α/4 and TRPC1β/4 channels but selectively activated TRPC4 homomeric channels. These findings demonstrate that TRPC1/4 channel shows dynamic gating property depending on TRPC1 isoform subtypes and receptor stimulation system. Therefore, careful discrimination of the specificity of TRPC1 isoforms and upstream activation system is important in thorough understanding of TRPC1 and TRPC1/4 channels.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Adding to this complexity, the TRPC1 gene has multiple splice variants. Isoformspecific (a and b, encoding long and short TRPC1 isoforms, respectively) TRPC1/TRPC4 heteromultimers were reported to have distinct activation mechanisms and gating properties (Kim et al, 2014a).…”

Critical roles of Gi/oproteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels

“…When overexpressed in HEK293 cells, both G q/11 -and G i/o -coupled muscarinic receptors (MRs) have been used to trigger TRPC4 currents (4). However, despite the presence of endogenous G q/11 -coupled MRs (SI Appendix, Fig.…”

“…In both heterologous and native systems, stimulating PLCβ via the G q/11 subgroup of G proteins is commonly used to activate TRPC channels. Recent studies, however, also suggest a role for G i/o subgroup of G proteins in the activation of TRPC4/C5 (2)(3)(4).…”

Identification and optimization of 2‐aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels

“…TRPC3/ C6/C7 can be directly activated by diacylglycerols (Hofmann et al, 1999). TRPC4/C5 appears to respond to receptors that activate Gi/o signalling in addition to the Gq/11-PLC pathway (Jeon et al, 2008;Otsuguro et al, 2008;Kim et al, 2014). Because PLC activation is commonly achieved by the stimulation of GPCRs or receptor tyrosine kinases, the TRPC channels are also referred to as receptor-operated channels (Plant and Schaefer, 2003).…”