Physiological Function and Characterization of TRPCs in Neurons

Abstract

Ca2+ entry is essential for regulating vital physiological functions in all neuronal cells. Although neurons are engaged in multiple modes of Ca2+ entry that regulates variety of neuronal functions, we will only discuss a subset of specialized Ca2+-permeable non-selective Transient Receptor Potential Canonical (TRPC) channels and summarize their physiological and pathological role in these excitable cells. Depletion of endoplasmic reticulum (ER) Ca2+ stores, due to G-protein coupled receptor activation, has been shown to activate TRPC channels in both excitable and non-excitable cells. While all seven members of TRPC channels are predominately expressed in neuronal cells, the ion channel properties, mode of activation, and their physiological responses are quite distinct. Moreover, many of these TRPC channels have also been suggested to be associated with neuronal development, proliferation and differentiation. In addition, TRPCs also regulate neurosecretion, long-term potentiation and synaptic plasticity. Similarly, perturbations in Ca2+ entry via the TRPC channels have been also suggested in a spectrum of neuropathological conditions. Hence, understanding the precise involvement of TRPCs in neuronal function and in neurodegenerative conditions would presumably unveil avenues for plausible therapeutic interventions for these devastating neuronal diseases.

Figure 1

Activation and regulation of TRPC channels. Binding of an agonist to RTKs or GPCR, initiate a signaling cascade, causing PLC-mediated hydrolysis of phosphatidylinositol (4,5) bisphosphate (PIP₂) to inositol (1,4,5)-triphosphate (IP₃) and diacylglycerol (DAG). DAG could directly activate certain TRPC channels. IP₃ binds to IP₃R, a ligand-gated ion channel, which leads to the release of Ca²⁺ from the internal ER stores. Depletion of Ca²⁺ from the internal stores, in turn, allows STIM1 to aggregate, followed by the activation of the TRPC or ORAI channels in the plasma membrane, which allows Ca²⁺ to enter the cell that orchestrates cellular functions. It also could depolarize the membrane and activate the voltage-dependent Ca²⁺ channel (VDCC). SERCA pumps are shown to work concertedly to maintain steady-state levels of intracellular Ca²⁺.