Emerging roles of canonical TRP channels in neuronal function

Abstract

Ca(2+) signaling in neurons is intimately associated with the regulation of vital physiological processes including growth, survival and differentiation. In neurons, Ca(2+) elicits two major functions. First as a charge carrier, Ca(2+) reveals an indispensable role in information relay via membrane depolarization, exocytosis, and the release of neurotransmitters. Second on a global basis, Ca(2+) acts as a ubiquitous intracellular messenger to modulate neuronal function. Thus, to mediate Ca(2+)-dependent physiological events, neurons engage multiple mode of Ca(2+) entry through a variety of Ca(2+) permeable plasma membrane channels. Here we discuss a subset of specialized Ca(2+)-permeable non-selective TRPC channels and summarize their physiological and pathological role in the context of excitable cells. TRPC channels are predominately expressed in neuronal cells and are activated through complex mechanisms, including second messengers and store depletion. A growing body of evidence suggests a prime contribution of TRPC channels in regulating fundamental neuronal functions. TRPC channels have been shown to be associated with neuronal development, proliferation and differentiation. In addition, TRPC channels have also been suggested to have a potential role in regulating neurosecretion, long term potentiation, and synaptic plasticity. During the past years, numerous seminal discoveries relating TRPC channels to neurons have constantly emphasized on the significant contribution of this group of ion channels in regulating neuronal function. Here we review the major groundbreaking work that has uniquely placed TRPC channels in a pivotal position for governing neuronal Ca(2+) signaling and associated physiological responses.

Fig. 31.1. General mechanism of TRPC channel activation

Agonist-mediated stimulation of RTKs or GPCRs initiate a signaling cascade leading to PLC-mediated hydrolysis of membrane bound PIP2, generating IP3 and DAG. DAG remains membrane associated, and could directly activate certain TRPC channels, whereas IP3 diffuses across the cytoplasm to activate its cognate-IP3 receptor. Activation of IP3R initiates ER Ca²⁺ store depletion. The Ca²⁺ sensor STIM1 senses the store-depletion and subsequently activates TRPC channels. IP3R also tends to interact with and activate homo/heteromeric TRPC channels. Additionally, the activation-dependant PM insertion of TRPC channels constitute a unique parameter for channel activation. PI3K and SNARE proteins are shown to positively regulate this trafficking. Thus, the resulting elevation in cytoplasmic [Ca²⁺]_cyt, ensuing activation of TRPC channels, orchestrate cellular functions. It is also depicted that TRPC-mediated non-selective ionic conductance could depolarize membrane and presumably activate voltage-gated Ca²⁺ channels (VGCC) as well as NCX. PMCA and SERCA pumps are shown to work concertedly to maintain steady-state levels of intracellular Ca²⁺