TRPC3 Channel Activity and Viability of Purkinje Neurons can be Regulated by a Local Signalosome.

Naveed Aslam,Farah Alvi

doi:10.3389/fmolb.2022.818682

Abstract

Canonical transient receptor potential channels (TRPC3) may play a pivotal role in the development and viability of dendritic arbor in Purkinje neurons. This is a novel postsynaptic channel for glutamatergic synaptic transmission. In the cerebellum, TRPC3 appears to regulate functions relating to motor coordination in a highly specific manner. Gain of TRPC3 function is linked to significant alterations in the density and connectivity of dendritic arbor in Purkinje neurons. TRPC3 signals downstream of class I metabotropic glutamate receptors (mGluR1). Moreover, diacylglycerol (DAG) can directly bind and activate TRPC3 molecules. Here, we investigate a key question: How can the activity of the TRPC3 channel be regulated in Purkinje neurons? We also explore how mGluR1 activation, Ca2+ influx, and DAG homeostasis in Purkinje neurons can be linked to TRPC3 activity modulation. Through systems biology approach, we show that TRPC3 activity can be modulated by a Purkinje cell (PC)–specific local signalosome. The assembly of this signalosome is coordinated by DAG generation after mGluR1 activation. Our results also suggest that purinergic receptor activation leads to the spatial and temporal organization of the TRPC3 signaling module and integration of its key effector molecules such as DAG, PKCγ, DGKγ, and Ca2+ into an organized local signalosome. This signaling machine can regulate the TRPC3 cycling between active, inactive, and desensitized states. Precise activity of the TRPC3 channel is essential for tightly regulating the Ca2+ entry into PCs and thus the balance of lipid and Ca2+ signaling in Purkinje neurons and hence their viability. Cell-type–specific understanding of mechanisms regulating TRPC3 channel activity could be key in identifying therapeutic targeting opportunities.

Highlights

The first discovery of a transient potential channel (TRP) was recorded in a Drosophila mutant displaying a transient receptor potential in response to steady light signals (Minke 1977; Montell, et al, 1985)
The minimal local regulatory model (Figures 1–3) we proposed for TRPC3 channel regulation in Purkinje cell (PC) is composed of five components: (1) second messenger Ca2+, which can be in three states, extracellular Ca20+, membrane Ca2I +, or cytosolic Ca2II+; (2) second messenger DAG, which can be in two states, nonphosphorylated at membrane or phosphorylated at membrane; (3) PKCIγ, which can be in one of four states, cytosolic dormant PKCIIγ, inactive membrane PKCIγ, active membrane PKCIγA, or active cytosolic PKCIIγA; (4) DGKγ, which can be in one of three states, cytosolic (DGKIIγ), inactive membrane (DGKIγ), or active phosphorylated membrane (DGKIγP); and (5) TRPC3 channel molecule, which can be in one of three states, membrane inactive (TRPC3), membrane active (TRPC3A), or membrane active phosphorylated (TRPC3AP)
Levels in the extracellular space above the basal levels. This model suggests that membrane depolarization–induced purinergic receptor activation generates DAG in the membrane compartment, which in turn binds with the inactive TRPC3 channel in the membrane compartment and activates it

Summary

Introduction

The first discovery of a transient potential channel (TRP) was recorded in a Drosophila mutant displaying a transient receptor potential in response to steady light signals (Minke 1977; Montell, et al, 1985). Observations based on two-photon imaging studies indicate that, despite the high permeability of the channel, TRPC3-mediated Ca2+ influx was only 8.8% of the overall mGluR1-mediated Ca2+ signal, suggesting only a minor contribution to Ca2+ release during physiological conditions (Henning, 2011) Despite this minor component, TRPC3-mediated Ca2+ influx seems to be critical, as behavioral studies show significant impairment of motor control in TRPC3-deficient mice compared with wild types (Hartmann et al, 2008; Hartmann and Konnerth 2009; Henning, 2011)

Methods

Results

Discussion

Conclusion