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The Molecular Diversity of TRPC Channels and Related Proteins

The cytosolic Ca2+ serves an intracellular mediator for many extracellular signals. The receptors coupling via heterotrimeric G proteins to different isoforms of phospholipase C (PLC) leads to the breakdown of phosphoinositide to inositol 1,4,5-phosphate (InsP3) and diacylglycerol (DAG).

After this reaction, a biphasic increase in cytosolic Ca2+ concentration occurs. The first stage results from transient InsP3-mediated release from intracellular stores. The second, more sustained phase, results from store-operated activation of Ca2+-permeable membrane channels.

The suggested role of this phase is refilling the intracellular Ca2+ stores or prolonging the response22-24.

Depending on the cell type, the second-phase Ca2+ channels may vary from highly selective Ca2+ channels to nonselective Ca2+-permeable channels3. The best studied store-operated Ca2+ current is Ca2+-release activated Ca2+ channel (CRAC), originally described in mast cells and T lymphocytes1,2.

The first step for molecular identification of storeoperated Ca2+ channels came from the study of Drosophila photoreceptors. In contrast to vertebrates, in insects, light activation of rhodopsin is coupled via a G protein to PLC, which leads to a biphasic Ca2+ entry. A mutant called trp (transient receptor potential) was shown to lack the second phase, light-induced current (LIC). It has been shown that trp codes a Ca2+-selective channel protein, TRP. Later, another closely related channel, TRPL, has been cloned. It forms a less selective Ca2+-permeable channel20, 21.

TRP channels (TRPCs) belong to the superfamily of cation channels with six transmembrane segments (see below). This superfamily includes voltage-gated K+, Na+, and Ca2+ channels, as well as cyclic nucleotide gated (CNG) channels, hyperpolarization-activated cyclic nucleotide gated (HCN) channels, and the most closely related group, polycystins (PKD)37,38 TRPC contain specific ankyrin domains in the cytosolic N-terminal part and proline-rich motif in the cytosolic C-terminal part.

The search of Caenorhabditis elegans genome database revealed 13 TRPC genes, that can be divided into three families4. The first is a family of long TRPC (LTRPC), with a reading frame of ~1600 residues. The second, short TRPC (STRPC), has a reading frame of ~900 residues. The more distant family, OTRPC, named after the homology with osm-9, the first cloned member of this family, also has a ~900 residue reading frame.

The suggested classification, based on C. elegans genome, seems to apply widely4. The Drosophila TRP and TRPL channels thus belong to STRPC family.

In mammals, seven members of this family, named TRPC1-7, have been cloned. While this family is more studied then the others, most data for mammalian TRPCs is based on heterologous expression system. There is good agreement that TRPCs are activated downstream of G-protein-coupled receptors, which induce PLC-mediated phosphoinositide breakdown. However, the downstream signaling pathways that finally activate TRPCs remain highly controversial. For nearly all of the functionally expressed TRPCs, there is at leas tone report proposing a store-operated mechanism of activation5-11. On the other hand, there is growing evidence for the involvement of store-independent pathways in the regulation of TRPC312-15, TRPC516, TRPC615,17, and TRPC718. For TRPL, TRPC3, and TRPC6, direct activators have been identified that stimulate the channels in a membrane-confined manner. Polyunsaturated fatty acids were shown to gate Drosophila TRPL19and DG to activate TRPC3, TRPC6, and TRPC715,18.

The tissue localization of TRPC differs greatly among the family members. TRPC1 is expressed ubiquitously, while TRPC3, TRPC4 and TRPC5 are almost exclusively localized in the brain11. In rat, TRPC2 is exclusively expressed in vomeronasal organ. Interestingly, in humans TRPC2 is a pseudogene, possibly in agreement with the lack of vomeronasal organ in higher primates29.

The C. elegans member of OTRPC family, osm-9, is involved in responses to odorants, high osmotic strength, and mechanical stimulation36. Similarly, the mammalian members of this family, VR133 and VRL134, form non-selective Ca2+-permeable channels activated by heat and other pain-producing stimuli35. Other members of this family, CaT1 (ECaC)30,31 and CaT239, seem to be involved in Ca2+ transport in epithelial cells32.

The function of the LTRPC family channels is completely unknown. One of mammalian LTRPC, melastatin, is found in melanocytes and its level is decreased in metastatic cells25. Another one, called TRPC7, but different from TRPC7 belonging to STRPC family19, has been recently described27. Another one, named MTR1, has been recently cloned26.

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