Several lines of evidence suggest that TRPA1 and TRPV1 mutually control the transduction of inflammation-induced noxious stimuli in sensory neurons. It was recently shown that certain TRPA1 properties are modulated by TRPV1. However, direct interaction between TRPA1 and TRPV1 as well as regulation of TRPA1 intrinsic characteristics by the TRPV1 channel have not been examined. To address these questions, we have studied a complex formation between TRPA1 and TRPV1 and characterized the influence of TRPV1 on single channel TRPA1-mediated currents. Co-immunoprecipitation analysis revealed direct interactions between TRPA1 and TRPV1 in an expression system as well as in sensory neurons. Data generated with total internal reflection fluorescence-based fluorescence resonance energy transfer indicate that a TRPA1-TRPV1 complex can be formed on the plasma membrane. . In summary, our results support the hypothesis that TRPV1 and TRPA1 form a complex and that TRPV1 influences intrinsic characteristics of the TRPA1 channel.Studies using TRPV1-and TRPA1-null mutant mouse lines (1-3), TRPA1 antisense knockdown (4), and in vivo effects of TRPA1 and TRPV1 antagonists (5, 6) have demonstrated that TRPV1 and TRPA1 channels play an important role in the development of hyperalgesia in certain inflammatory and neuropathic pain models.Like most mammalian TRP channels, TRPV1 and possibly TRPA1 function as homotetramers (7,8). In addition, TRP channels belonging to the same subfamilies (i.e. the V, C, M, or P subfamilies) can interact and form heteromers (7). It has also been noted that most heteromeric TRP channel complexes appear to consist of subunit combinations only within relatively narrow confines of phylogenetic subfamilies (7). Recent reports indicate that the native TRPA1 channel has characteristics different from those of homomeric TRPA1 expressed in cell lines (9, 10). Interestingly, these characteristics of TRPA1 are restored similarly to characteristics recorded from native cells when TRPA1 and TRPV1 are co-expressed in sensory neurons or expression systems (9). Further, there is evidence suggesting that these channels could heterologously interregulate each other's activities and characteristics. Thus, pharmacological cross-desensitization between capsaicin and mustard oil responses was noted and characterized (10 -13). Transmission of inflammatory stimuli by nociceptors (i.e. damage-sensing sensory neurons) is also mutually controlled by TRPA1 and TRPV1 channels (1, 3). It was suggested that this functional interaction between TRPV1 and TRPA1 could occur either indirectly via recruitment of second messengers, such as intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (1, 14), or directly, involving interaction of these channels within a complex (9,15).Given previously published results, the present study assesses the following questions: (i) whether TRPA1 and TRPV1 channels could assemble into a complex on the plasma membrane; (ii) whether interactions of TRPA1 with TRPV1 affect intrinsic (i.e. single channel) characteristics of TRPA1...
Background: Mineralocorticoid aldosterone controls ENaC-mediated Na ϩ reabsorption in the distal nephron.
Injury to podocytes is considered a major contributor to diabetic kidney disease: their loss causes proteinuria and progressive glomerulosclerosis. Podocyte depletion may result from improper calcium handling due to abnormal activation of the calcium permeant TRPC (Transient Receptor Potential Canonical) channels. Angiotensin II (Ang II) levels are found to be elevated in diabetes; furthermore, it was reported that Ang II causes activation of TRPC6 in podocytes. We hypothesized here that Ang II-mediated calcium influx is aggravated in the podocytes under the conditions of type 1 diabetic nephropathy (DN). Diabetes was induced in the Dahl Salt-Sensitive rats by an injection of streptozotocin (STZ-SS). Eleven weeks post treatment was sufficient for the animals to develop hyperglycemia, excessive urination, weight loss, microalbuminuria, nephrinuria and display renal histological lesions typical for patients with DN. Patch-clamp electrophysiology performed on podocytes of the freshly isolated glomeruli showed enhanced basal TRPC channel activity in the STZ-SS rats, and increased response to Ang II; total calcium influx triggered by Ang II application was also augmented in podocytes of these rats. Our studies have a strong potential for advancing the understanding of TRPC-mediated effects on podocytopenia in DN initiation.
A key role for podocytes in the pathogenesis of proteinuric renal diseases has been established. Angiotensin II causes depolarization and increased intracellular calcium concentration in podocytes; members of the cation TRPC channels family, particularly TRPC6, are proposed as proteins responsible for calcium flux. Angiotensin II evokes calcium transient through TRPC channels and mutations in the gene encoding the TRPC6 channel result in the development of focal segmental glomerulosclerosis. Here we examined the effects of angiotensin II on intracellular calcium ion levels and endogenous channels in intact podocytes of freshly isolated decapsulated mouse glomeruli. An ion channel with distinct TRPC6 properties was identified in wild type, but was absent in TRPC6 knockout mice. Single channel electrophysiological analysis found that angiotensin II acutely activated native TRPC-like channels in both podocytes of freshly isolated glomeruli and TRPC6 channels transiently overexpressed in CHO cells; the effect was mediated by changes in the channel open probability. Angiotensin II evoked intracellular calcium transients in the wild type podocytes, which was blunted in TRPC6 knockout glomeruli. Pan-TRPC inhibitors gadolinium and SKF 96365 reduced the response in wild type glomerular epithelial cells, whereas the transient in TRPC6 knockout animals was not affected. Thus, angiotensin II-dependent activation of TRPC6 channels in podocytes may have a significant role in the development of kidney diseases.
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