Transient Receptor Potential-Canonical (TRPC) channels are mammalian homologs of Transient Receptor Potential (TRP), a Ca(2+)-permeable channel involved in the phospholipase C-regulated photoreceptor activation mechanism in Drosophila. The seven mammalian TRPCs constitute a family of channels which have been proposed to function as store-operated as well as second messenger-operated channels in a variety of cell types. TRPC channels, together with other more distantly related channel families, make up the larger TRP channel superfamily. This review summarizes recent findings on the structure, regulation and function of the apparently ubiquitous TRPC cation channels.

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Depletion of intracellular Ca2+ stores induces Ca2+ influx across the plasma membrane through store-operated channels (SOCs). This store-operated Ca2+ influx is important for the replenishment of the Ca2+ stores, and is also involved in many signaling processes by virtue of the ability of intracellular Ca2+ to act as a second messenger. For many years, the molecular identities of particular SOCs, as well as the signaling mechanisms by which these channels are activated, have been elusive. Recently, however, the mammalian proteins STIM1 and Orai1 were shown to be necessary for the activation of store-operated Ca2+ entry in a variety of mammalian cells. Here we present molecular, pharmacological, and electrophysiological properties of SOCs, with particular focus on the roles that STIM1 and Orai1 may play in the signaling processes that regulate various pathways of store-operated entry.

Mammalian Trp proteins are candidates for plasma membrane calcium channels regulated by receptor activation or by intracellular calcium store depletion [capacitative calcium entry (CCE)]. One extensively investigated member of the Trp family, the human Trp3 (hTrp3), behaves as a receptor-activated, calcium-permeable, nonselective cation channel when expressed in cell lines and does not appear to be activated by store depletion. Nonetheless, there is good evidence that Trp3 can be regulated by interacting with inositol trisphosphate receptors (IP3Rs), reminiscent of the conformational coupling mode of CCE. To investigate the role of Trp3 in CCE, and its regulation by IP3R, we transiently expressed hTrp3 in the wild-type DT40 chicken B lymphocyte cell line and its variant lacking IP3R. Expression of hTrp3 in either wild-type or IP3R-knockout cells did not increase basal membrane permeability, but resulted in a substantially greater divalent cation entry after thapsigargin-induced store depletion. This hTrp3-dependent divalent cation entry was significantly greater in the wild type than in IP3R-knockout cells. Thus, it appears that in this cell line, hTrp3 forms channels that are store-operated by both IP3R-dependent and IP 3R-independent mechanisms. Trp3, or one of its structural relatives, is a candidate for the store-operated, nonselective cation channels observed in smooth muscle cells and other cell types.

Functional status was an independent predictor for short- and long-term mortality in hospitalized patients whereas CAP severity predicted functional decline. Severity indices for CAP should possibly thus be adjusted in the elderly population, taking functional status assessment into account.

Subcutaneous adipocyte apoptosis occurs in lipoatrophic areas of patients with HIV-1 protease inhibitor-associated lipodystrophy.

We examined the roles of inositol 1,4,5-trisphosphate (IP 3 ) receptors (IP 3 R) in calcium signaling using DT40 B lymphocytes, and a variant lacking the three IP 3 R isoforms (IP 3 R-KO). In wild-type cells, B cell receptor (BCR) stimulation activates a cation entry route that exhibits signi®cantly greater permeability to Ba 2+ than does capacitative calcium entry. This cation entry is absent in IP 3 R-KO cells. Expression of the type-3 IP 3 R (IP 3 R-3) in the IP 3 R-KO cells rescued not only agonist-dependent release of intracellular Ca 2+ , but also Ba 2+ in¯ux following receptor stimulation. Similar results were obtained with an IP 3 R-3 mutant carrying a conservative point mutation in the selectivity ®lter region of the channel (D2477E); however, an IP 3 R-3 mutant in which this same aspartate was replaced by alanine (D2477A) failed to restore either BCR-induced Ca 2+ release or receptor-dependent Ba 2+ entry. These results suggest that in DT40 B lymphocytes, BCR stimulation activates a novel cation entry across the plasma membrane that depends upon, or is mediated by, fully functional IP 3 R.

Studies on the mechanism of activation of canonical transient receptor potential (TRPC) channels have often yielded conflicting results. In the current study, we have investigated the influence of expression level on the mode of regulation of TRPC3 channels. At relatively low levels of expression in DT40 chicken B-lymphocytes, TRPC3 was activated by the depletion of Ca 2؉ stores. Expression was increased by either transfecting with a 10-fold greater concentration of plasmid or transfecting with TRPC3 under control of a more efficient avian ␤-actin promoter. At higher levels of expression, TRPC3 was no longer store-operated but could be activated through receptor-coupled phospholipase C. Under these expression conditions, TRPC3 was efficiently activated in DT40 cells lacking inositol 1,4,5-trisphosphate receptors. The Ca 2؉ store-operated channels formed upon expression of TRPC3 at limited levels were blocked by gadolinium; the receptor-activated channels formed upon expression of higher levels of TRPC3 were insensitive to gadolinium. These findings indicate that a single ion channel protein can form or contribute to the formation of channels regulated in two very distinct ways, i.e. either by phospholipase C-derived messengers or Ca 2؉ store-depletion. The mechanism of regulation of the channels depends on their level of expression.In most nonexcitable cells, calcium signaling initiated through cell membrane receptors coupled to phospholipase C (PLC) 1 results in production of inositol 1,4,5-trisphosphate (IP 3 ) (1, 2). IP 3 induces the release of Ca 2ϩ from the endoplasmic reticulum and the subsequent influx of Ca 2ϩ across the plasma membrane through the capacitative calcium entry (CCE) or the store-operated calcium entry pathway (3-6). Although CCE has been widely studied in diverse cell types, the molecular identity of store-operated channels (SOCs) and the signal by which store emptying activates those channels remain uncertain. Mammalian homologues of the Drosophila transient receptor potential (TRP) channel have been proposed as candidates for SOCs (7,8). Among the members of the canonical TRP (TRPC) subfamily (designated TRPC1 through TRPC7), human TRPC3, first cloned by Zhu et al. (9), has been shown in many heterologous expression systems to behave as a receptor-activated channel with constitutive activity that cannot be further increased by Ca 2ϩ store depletion (10 -12). Furthermore, Hofmann et al. (13) showed that TRPC3 and its structural relative TRPC6 can be activated by diacylglycerols (DAGs), providing a possible mechanism of activation of these channels by phospholipase C-linked receptors independent of IP 3 and store depletion.We recently demonstrated that TRPC3 is regulated by store depletion when transiently expressed in DT40 chicken B-lymphocytes (14), and we proposed TRPC3 as a candidate for store-operated, non-selective cation channels. However, Venkatachalam et al. (15) reported that, in this same cell line, TRPC3 behaves as a receptor-activated channel with no dependence on the deple...