Modulation and Regulation of Canonical Transient Receptor Potential 3 (TRPC3) Channels

Abstract

Canonical transient receptor potential 3 (TRPC3) channel is a non-selective cation permeable channel that plays an essential role in calcium signalling. TRPC3 is highly expressed in the brain and also found in endocrine tissues and smooth muscle cells. The channel is activated directly by binding of diacylglycerol downstream of G-protein coupled receptor activation. In addition, TRPC3 is regulated by endogenous factors including Ca2+ ions, other endogenous lipids, and interacting proteins. The molecular and structural mechanisms underlying activation and regulation of TRPC3 are incompletely understood. Recently, several high-resolution cryogenic electron microscopy structures of TRPC3 and the closely related channel TRPC6 have been resolved in different functional states and in the presence of modulators, coupled with mutagenesis studies and electrophysiological characterisation. Here, we review the recent literature which has advanced our understanding of the complex mechanisms underlying modulation of TRPC3 by both endogenous and exogenous factors. TRPC3 plays an important role in Ca2+ homeostasis and entry into cells throughout the body, and both pathological variants and downstream dysregulation of TRPC3 channels have been associated with a number of diseases. As such, TRPC3 may be a valuable therapeutic target, and understanding its regulatory mechanisms will aid future development of pharmacological modulators of the channel.

Heterogeneity in slow synaptic transmission diversifies Purkinje cell timing

“…Thus, we identified more than one molecular correlate of heterogeneity across lobules, within known components of mGluR-TRPC3 signaling pathways. In addition, these signaling components are likely to interact with each other (Cole and Becker, 2023). Moreover, our bioinformatic analysis by separating cells from different lobules obscures the within-lobule heterogeneity observed both in previous studies of the Purkinje cell transcriptome and in our data (Kozareva et al, 2021).…”

“…However, we found that the non-competitive mGluR1 antagonist CPCCOEt (Hartmann et al, 2008) blocked slow EPSCs in all three regions (Figure S4a), arguing against this possibility. Downstream of mGluR1, the slow EPSC is mediated by the nonselective cation channel TRPC3 (Hartmann et Cole and Becker, 2023), which both partially block the slow EPSC, allowing us to measure the kinetics of the remaining current. We found that the magnitude of the slow EPSC was consistently reduced by genistein and by SKF96365 across lobules, but there was no shift in timing that could explain the differences between lobules (Figure S4b-e).…”

“…The characteristically prolonged time-course of the slow EPSC is related to the associated G-protein dependent signaling cascade (Figure 5a) (Brasnjo and Otis, 2001; Hartmann, Henning and Konnerth, 2011; Kano and Watanabe, 2017; Hirai and Kano, 2018; Cole and Becker, 2023). However, the signaling pathways connecting mGluR1 and TRPC3 signaling, and its regulation, are not fully understood (Cole and Becker, 2023). In spite of this, we wanted to identify candidate molecular players underlying the diversity of slow EPSCs across lobules.…”

“…However, even zebrin positive cells (green hollow circles) in lobule IV/V had a characteristically shorter time of peak and zebrin-negative cells (black hollow circles) in lobule X and flocculus had a delayed time of peak. interest and focused on molecular candidates related to the mGluR1-TRPC3 pathway (Figure 5b) (Brasnjo and Otis, 2001; Hartmann, Henning and Konnerth, 2011; Kano and Watanabe, 2017; Hirai and Kano, 2018; Cole and Becker, 2023). Comparison of gene expression demonstrated statistically significant differences across lobules.…”

“…The metabotropic arm of PF input triggers an intracellular signaling cascade, and a slow excitatory postsynaptic current (slow EPSC) through the transient receptor potential channel TRPC3 (Hartmann et al, 2008;Hartmann, Henning and Konnerth, 2011;Henning, 2011;Hartmann and Konnerth, 2015). mGluR1 signaling (Aiba et al, 1994;Ichise et al, 2000;Hartmann et al, 2008;Lüscher and Huber, 2010;Becker, 2014; Crupi, Impellizzeri and Cuzzocrea, 2019; Cole and Becker, 2023) and TRPC3-dependent currents (Hartmann et al, 2008;Hartmann, Henning and Konnerth, 2011;Cole and Becker, 2023) are both essential for normal cerebellar function. However, heterogeneity of mGluR1-mediated slow synaptic transmission across lobules has never yet been investigated.…”