scholarly journals Common mechanisms regulating dark noise and quantum bump amplification in Drosophila photoreceptors

2013 ◽  
Vol 109 (8) ◽  
pp. 2044-2055 ◽  
Author(s):  
Brian Chu ◽  
Che-Hsiung Liu ◽  
Sukanya Sengupta ◽  
Amit Gupta ◽  
Padinjat Raghu ◽  
...  
Keyword(s):  
G Protein ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Diacylglycerol Kinase ◽  
Scaffolding Protein ◽  
Light Responses ◽  
Α Subunit ◽  
High Quantum Efficiency ◽  
Dark Noise

Absolute visual thresholds are limited by “dark noise,” which in Drosophila photoreceptors is dominated by brief (∼10 ms), small (∼2 pA) inward current events, occurring at ∼2/s, believed to reflect spontaneous G protein activations. These dark events were increased in rate and amplitude by a point mutation in myosin III (NINAC), which disrupts its interaction with the scaffolding protein, INAD. This phenotype mimics that previously described in null mutants of ninaC (no inactivation no afterpotential; encoding myosin III) and an associated protein, retinophilin ( rtp). Dark noise was similarly increased in heterozygote mutants of diacylglycerol kinase ( rdgA/+). Dark noise in ninaC, rtp, and rdgA/+ mutants was greatly suppressed by mutations of the Gq α-subunit ( Gα q) and the major light-sensitive channel ( trp) but not rhodopsin. ninaC, rtp, and rdgA/+ mutations also all facilitated residual light responses in Gα q and PLC hypomorphs. Raising cytosolic Ca2+ in the submicromolar range increased dark noise, facilitated activation of transient receptor potential (TRP) channels by exogenous agonist, and again facilitated light responses in Gα q hypomorphs. Our results indicate that RTP, NINAC, INAD, and diacylglycerol kinase, together with a Ca2+-dependent threshold, share common roles in suppressing dark noise and regulating quantum bump generation; consequently, most spontaneous G protein activations fail to generate dark events under normal conditions. By contrast, quantum bump generation is reliable but delayed until sufficient G proteins and PLC are activated to overcome threshold, thereby ensuring generation of full-size bumps with high quantum efficiency.

scholarly journals The nonselective cation channel TRPV4 inhibits angiotensin II receptors

2020 ◽  
Vol 295 (29) ◽  
pp. 9986-9997
Author(s):  
Nicholas W. Zaccor ◽  
Charlotte J. Sumner ◽  
Solomon H. Snyder
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Trp Channel ◽  
Luciferase Assay ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Transient Receptor

G-protein–coupled receptors (GPCRs) are a ubiquitously expressed family of receptor proteins that regulate many physiological functions and other proteins. They act through two dissociable signaling pathways: the exchange of GDP to GTP by linked G-proteins and the recruitment of β-arrestins. GPCRs modulate several members of the transient receptor potential (TRP) channel family of nonselective cation channels. How TRP channels reciprocally regulate GPCR signaling is less well-explored. Here, using an array of biochemical approaches, including immunoprecipitation and fluorescence, calcium imaging, phosphate radiolabeling, and a β-arrestin–dependent luciferase assay, we characterize a GPCR–TRP channel pair, angiotensin II receptor type 1 (AT1R), and transient receptor potential vanilloid 4 (TRPV4), in primary murine choroid plexus epithelial cells and immortalized cell lines. We found that AT1R and TRPV4 are binding partners and that activation of AT1R by angiotensin II (ANGII) elicits β-arrestin–dependent inhibition and internalization of TRPV4. Activating TRPV4 with endogenous and synthetic agonists inhibited angiotensin II–mediated G-protein–associated second messenger accumulation, AT1R receptor phosphorylation, and β-arrestin recruitment. We also noted that TRPV4 inhibits AT1R phosphorylation by activating the calcium-activated phosphatase calcineurin in a Ca2+/calmodulin–dependent manner, preventing β-arrestin recruitment and receptor internalization. These findings suggest that when TRP channels and GPCRs are co-expressed in the same tissues, many of these channels can inhibit GPCR desensitization.

scholarly journals Mice Lacking Homer 1 Exhibit a Skeletal Myopathy Characterized by Abnormal Transient Receptor Potential Channel Activity

2008 ◽  
Vol 28 (8) ◽  
pp. 2637-2647 ◽  
Author(s):  
Jonathan A. Stiber ◽  
Zhu-Shan Zhang ◽  
Jarrett Burch ◽  
Jerry P. Eu ◽  
Sarah Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Scaffolding Protein ◽  
Channel Activity ◽  
Skeletal Muscle Function ◽  
Cross Sectional ◽  
Transient Receptor ◽  
Duchenne's Muscular Dystrophy

ABSTRACT Transient receptor potential (TRP) channels are nonselective cation channels, several of which are expressed in striated muscle. Because the scaffolding protein Homer 1 has been implicated in TRP channel regulation, we hypothesized that Homer proteins play a significant role in skeletal muscle function. Mice lacking Homer 1 exhibited a myopathy characterized by decreased muscle fiber cross-sectional area and decreased skeletal muscle force generation. Homer 1 knockout myotubes displayed increased basal current density and spontaneous cation influx. This spontaneous cation influx in Homer 1 knockout myotubes was blocked by reexpression of Homer 1b, but not Homer 1a, and by gene silencing of TRPC1. Moreover, diminished Homer 1 expression in mouse models of Duchenne's muscular dystrophy suggests that loss of Homer 1 scaffolding of TRP channels may contribute to the increased stretch-activated channel activity observed in mdx myofibers. These findings provide direct evidence that Homer 1 functions as an important scaffold for TRP channels and regulates mechanotransduction in skeletal muscle.

Intragastric administration of capsiate, a transient receptor potential channel agonist, triggers thermogenic sympathetic responses

2011 ◽  
Vol 110 (3) ◽  
pp. 789-798 ◽  
Author(s):  
Kaori Ono ◽  
Masako Tsukamoto-Yasui ◽  
Yoshiko Hara-Kimura ◽  
Naohiko Inoue ◽  
Yoshihito Nogusa ◽  
...  
Keyword(s):  
Sympathetic Nerve ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Low Frequency ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Intragastric Administration ◽  
Brown Adipose ◽  
Reflex Arc ◽  
Transient Receptor

The sympathetic thermoregulatory system controls the magnitude of adaptive thermogenesis in correspondence with the environmental temperature or the state of energy intake and plays a key role in determining the resultant energy storage. However, the nature of the trigger initiating this reflex arc remains to be determined. Here, using capsiate, a digestion-vulnerable capsaicin analog, we examined the involvement of specific activation of transient receptor potential (TRP) channels within the gastrointestinal tract in the thermogenic sympathetic system by measuring the efferent activity of the postganglionic sympathetic nerve innervating brown adipose tissue (BAT) in anesthetized rats. Intragastric administration of capsiate resulted in a time- and dose-dependent increase in integrated BAT sympathetic nerve activity (SNA) over 180 min, which was characterized by an emergence of sporadic high-activity phases composed of low-frequency bursts. This increase in BAT SNA was abolished by blockade of TRP channels as well as of sympathetic ganglionic transmission and was inhibited by ablation of the gastrointestinal vagus nerve. The activation of SNA was delimited to BAT and did not occur in the heart or pancreas. These results point to a neural pathway enabling the selective activation of the central network regulating the BAT SNA in response to a specific stimulation of gastrointestinal TRP channels and offer important implications for understanding the dietary-dependent regulation of energy metabolism and control of obesity.

scholarly journals Characterization Of Selective TRPM8 Ligands And Their Structure Activity Response (S.A.R) Relationship

2010 ◽  
Vol 13 (2) ◽  
pp. 242 ◽  
Author(s):  
Muhammad Azhar Sherkheli ◽  
Angela K. Vogt-Eisele ◽  
Daniel Bura ◽  
Leopoldo R. Beltrán Márques ◽  
Günter Gisselmann ◽  
...  
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Parent Compound ◽  
Receptor Potential ◽  
Basic Research ◽  
Fold Increase ◽  
Ring Structure ◽  
Sensory Nerves ◽  
Transient Receptor Potential Melastatin

PURPOSE: Transient receptor potential melastatin-8 (TRPM8) is an ion channel expressed extensively in sensory nerves, human prostate and overexpressed in a variety of cancers including prostate, breast, lung, colon and skin melanomas. It is activated by innoxious cooling and chemical stimuli. TRPM8 activation by cooling or chemical agonists is reported to induce profound analgesia in neuropathic pain conditions. Known TRPM8 agonists like menthol and icilin cross-activate other thermo-TRP channels like TRPV3 and TRPA1 and mutually inhibit TRPM8. This limits the usefulness of menthol and icilin as TRPM8 ligands. Consequently, the identification of selective and potent ligands for TRPM8 is of high relevance both in basic research and for therapeutic applications. In the present investigation, a group of menthol derivates was characterized. These ligands are selective and potent agonists of TRPM8. Interestingly they do not activate other thermo-TRPs like TRPA1, TRPV1, TRPV2, TRPV3 and TRPV4. These ion channels are also nociceptors and target of many inflammatory mediators. METHODS: Investigations were performed in a recombinant system: Xenopus oocytes microinjected with cRNA of gene of interest were superfused with the test substances after initial responses of known standard agonists. Evoked currents were measured by two-electrode voltage clamp technique. RESULTS: The newly characterized ligands possess an up to six-fold higher potency (EC50 in low µM) and an up to two-fold increase in efficacy compared to the parent compound menthol. In addition, it is found that chemical derivatives of menthol like CPS-368, CPS-369, CPS-125, WS-5 and WS-12 are the most selective ligands for TRPM8. The enhanced activity and selectivity seems to be conferred by hexacyclic ring structure present in all ligands as substances like WS-23 which lack this functional group activate TRPM8 with much lower potency (EC50 in mM) and those with pentacyclcic ring structure (furanone compounds) are totally inactive. CONCLUSION: The new substances activate TRPM8 with a higher potency, efficacy and specificity than menthol and will thus be of importance for the development of pharmacological agents suitable for treatment and diagnosis of certain cancers and as analgesics. STATEMENT OF NOVELTY: The new compounds have an unmatched specificity for TRPM8 ion channels with additional display of high potency and efficacy. Thus these substances are better pharmacological tools for TRPM8 characterization then known compounds and it is suggested that these menthol-derivates may serve as model substances for the development of TRPM8 ligands.

scholarly journals Differential role of TRP channels in prostate cancer

2007 ◽  
Vol 35 (1) ◽  
pp. 133-135 ◽  
Author(s):  
N. Prevarskaya ◽  
M. Flourakis ◽  
G. Bidaux ◽  
S. Thebault ◽  
R. Skryma
Keyword(s):  
Prostate Cancer ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Clinical Problem ◽  
Tissue Growth ◽  
Transient Receptor Potential Channels ◽  
Potential Channels ◽  
Differentiation And Proliferation

A major clinical problem with PC (prostate cancer) is the cell's ability to survive and proliferate upon androgen withdrawal. Indeed, deregulated cell differentiation and proliferation, together with the suppression of apoptosis, provides the condition for abnormal tissue growth. Here, we examine the differential role of TRP (transient receptor potential) channels in the control of Ca2+ homoeostasis and growth of PC cells.

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