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Phosphatidylinositol-4,5-bisphosphate (PIP) has emerged as a versatile regulator of TRP ion channels. In many cases, the regulation involves interactions of channel proteins with the lipid itself independent of its hydrolysis products. The functions of the regulation mediated by such interactions are diverse. Some TRP channels absolutely require PIP for functioning, while others are inhibited. A change of gating is common to all, endowing the lipid a role for modulation of the sensitivity of the channels to their physiological stimuli. The activation of TRP channels may also influence cellular PIP levels via the influx of Ca through these channels. Depletion of PIP in the plasma membrane occurs upon activation of TRPV1, TRPM8, and possibly TRPM4/5 in heterologous expression systems, whereas resynthesis of PIP requires Ca entry through the TRP/TRPL channels in photoreceptors. These developments concerning PIP regulation of TRP channels reinforce the significance of the PLC signaling cascade in TRP channel function, and provide further perspectives for understanding the physiological roles of these ubiquitous and often enigmatic channels.

Ca, nitric oxide (NO), and protein kinase G (PKG) are important signaling molecules that play pivotal roles in many physiological processes such as vascular tone control, platelet activation, and synaptic plasticity. TRPC channels allow Ca influx, thus contributing to the production of NO, which subsequently stimulates PKG. It has been demonstrated that PKG can phosphorylate human TRPC3 at Thr-11 and Ser-263 and that this phosphorylation inactivates TRPC3. These two PKG phosphorylation sites, Thr-11 and Ser-263 in human TRPC3, are conserved in other members of the TRPC3/6/7 subfamily, suggesting that PKG may also phosphorylate TRPC6 and TRPC7. In addition, protein kinase C (PKC) also inactivates TRPC3, partly through activating PKG. The PKG-mediated inhibition of TRPC channels may provide a feedback control for the fine tuning of [Ca]i levels and protect the cells from the detrimental effects of excessive [Ca]i and/or NO.

Transient receptor potential (TRP) channels are members of a relatively newly described family of cation channels that display a wide range of properties and mechanisms of activation. The exact physiological function and regulation of most of these channels have not yet been conclusively determined. Studies over the past decade have revealed important features of the channels that contribute to their function. These include homomeric interactions between TRP monomers, selective heteromeric interactions within members of the same subfamily, interactions of TRPs with accessory proteins and assembly into macromolecular signaling complexes, and regulation within functionally distinct cellular microdomains. Further, distinct constitutive and regulated vesicular trafficking mechanisms have a critical role not only in controlling the surface expression of TRP channels but also their activation in response to stimuli. A number of cellular components such as cytoskeletal and scaffolding proteins also contribute to TRP channel trafficking. Thus, mechanisms involved in the assembly and trafficking of TRP channels control their plasma membrane expression and critically impact their function and regulation.

TRP channels, in particular the TRPC and TRPV subfamilies, have emerged as important constituents of the receptor-activated Ca influx mechanism triggered by hormones, growth factors, and neurotransmitters through activation of phospholipase C (PLC). Several TRPC channels are also activated by passive depletion of endoplasmic reticulum (ER) Ca. Although in several studies the native TRP channels faithfully reproduce the respective recombinant channels, more often the properties of Ca entry and/or the store-operated current are strikingly different from that of the TRP channels expressed in the same cells. The present review aims to discuss this disparity in the context of interaction of TRPC channels with auxiliary proteins that may alter the permeation and regulation of TRPC channels.

TRPC channels are ubiquitously expressed among cell types and mediate signals in response to phospholipase C (PLC)-coupled receptors. TRPC channels function as integrators of multiple signals resulting from receptor-induced PLC activation, which catalyzes the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP) to produce inositol 1,4,5-trisphosphate (InsP) and diacylglycerol (DAG). InsP depletes Ca stores and TRPC3 channels can be activated by store-depletion. InsP also activates the InsP receptor, which may undergo direct interactions with the TRPC3 channel, perhaps mediating store-dependence. The other PLC product, DAG, has a direct non-PKC-dependent activating role on TRPC3 channels likely by direct binding. DAG also has profound effects on the TRPC3 channel through PKC. Thus PKC is a powerful inhibitor of most TRPC channels and DAG is a dual regulator of the TRPC3 channel. PLC-mediated DAG results in rapid channel opening followed later by a slower DAG-induced PKC-mediated deactivation of the channel. The decreased level of PIP from PLC activation also has an important modifying action on TRPC3 channels. Thus, the TRPC3 channel and PLCγ form an intermolecular PH domain that has high specificity for binding PIP. This interaction allows the channel to be retained within the plasma membrane, a further operational control factor for TRPC3. As nonselective cation channels, TRPC channel opening results in the entry of both Na and Ca ions. Thus, while they may mediate Ca entry signals, TRPC channels are also powerful modifiers of membrane potential.

The canonical transient receptor potential (TRPC) cation channels are mammalian homologs of the photoreceptor channel TRP in . All seven TRPCs (TRPC1 through TRPC7) can be activated through Gq/11 receptors or receptor tyrosine kinase (RTK) by mechanisms downstream of phospholipase C. The last decade saw a rapidly growing interest in understanding the role of TRPC channels in calcium entry pathways as well as in understanding the signal(s) responsible for TRPC activation. TRPC channels have been proposed to be activated by a variety of signals including store depletion, membrane lipids, and vesicular insertion into the plasma membrane. Here we discuss recent developments in the mode of activation as well as the pharmacological and electrophysiological properties of this important and ubiquitous family of cation channels.