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.

Neurological and Motor Disorders: Neuronal Store-Operated Ca2+ Signaling: An Overview and Its Function

“…In contrast, a recent report showed that STIM2 is essential for the SOCE in hippocampal neurons and downregulation of STIM2 leads to massive loss of neurons. Consistent with this, samples of AD patients also showed a decrease in STIM2, but not STIM1 (Sun et al 2014). However, still the molecular identity of the Ca 2+ channel that could contribute to these results (Orai vs TRPC) is not yet established.…”

“…Changes in intracellular Ca 2+ concentration stimulate a number of intracellular events and could either trigger or inhibit the cell death process (Berridge et al 2000; Putney 2003). Importantly, disturbances in Ca 2+ homeostasis have been implicated in many neurodegenerative diseases such as, PD, AD, and HD (Albers and Beal 2000; Bollimuntha et al 2005b; O’Bryant et al 2009; Zuccato and Cattaneo 2007; Zuccato and Cattaneo 2009; Sun et al 2014). It is not surprising that disturbances in Ca 2+ signaling pathways underlie neuronal loss, since many factors involved in neuronal function are dependent on Ca 2+ signaling (Berridge et al 2000; Putney 2003).…”

“…SOCE has also been identified in many types of excitable cells and is important in maintaining Ca 2+ homeostasis (Majewski and Kuznicki 2015; Sun et al 2014). For a long time neuronal cells have been thought not to have a SOCE pathway (Friel and Tsien 1992), since these cells have the voltage-gated Ca 2+ channels and the receptor activated Ca 2+ channels such as glutamate and AMPA receptors as their prime Ca 2+ influx components.…”

“…Importantly, both Orai and STIM proteins are expressed in skeletal and brain tissues, albeit with different expression patters (Kraft 2015) and STIM2-deficient mice were protected from cerebral damage after ischemic stroke (Berna-Erro et al 2009). However, another study showed that loss of STIM2 induced a massive neuronal loss in the hippocampal region (Sun et al 2014), suggesting that STIM2 could have differential role on different cells.…”

Pyrazolopyrimidines as Potent Stimulators for Transient Receptor Potential Canonical 3/6/7 Channels

“…2 So far, the majority of studies on TRPC channels have focused on their roles in mediating Ca 2+ and Na + influx after the stimulation of phospholipase C (PLC) either by G protein-coupled receptors that signal through the G q/11 subgroup of heterotrimeric G proteins or by receptor tyrosine kinases. 3 These activities cause membrane depolarization and a sustained increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ), which are important for a plethora of cellular functions in many physiological systems. 4 On the other hand, a few studies also implicated TRPC channel expression and function in intracellular membranes, 5 suggesting that very diverse cellular activities may be regulated by these channels.…”