Molecular and Cellular Aspects of Atherosclerosis: Emerging Roles of TRPC Channels

The mechanism(s) of olfactory transduction in invertebrates remains to be fully understood. In lobster olfactory receptor neurons (ORNs), a nonselective sodium-gated cation (SGC) channel, a presumptive transient receptor potential (TRP)C channel homolog, plays a crucial role in olfactory transduction, at least in part by amplifying the primary transduction current. To better determine the functional role of the channel, it is important to selectively block the channel independently of other elements of the transduction cascade, causing us to search for specific pharmacological blockers of the SGC channel. Given evidence that the Na+/Ca2+ exchange inhibitor, KB-R7943, blocks mammalian TRPC channels, we studied this probe as a potential blocker of the lobster SGC channel. KB-R7943 reversibly blocked the SGC current in both inside- and outside-out patch recordings in a dose- and voltage-dependent manner. KB-R7943 decreased the channel open probability without changing single channel amplitude. KB-R7943 also reversibly and in a dose-dependent manner inhibited both the odorant-evoked discharge of lobster ORNs and the odorant-evoked whole cell current. Our findings strongly imply that KB-R7943 potently blocks the lobster SGC channel and likely does so directly and not through its ability to block the Na+/Ca2+ exchanger.

Download Full-text

NMDA Receptor-Dependent Synaptic Activation of TRPC Channels in Olfactory Bulb Granule Cells

Journal of Neuroscience ◽

10.1523/jneurosci.3753-11.2012 ◽

2012 ◽

Vol 32 (17) ◽

pp. 5737-5746 ◽

Cited By ~ 43

Author(s):

O. Stroh ◽

M. Freichel ◽

O. Kretz ◽

L. Birnbaumer ◽

J. Hartmann ◽

...

Keyword(s):

Nmda Receptor ◽

Olfactory Bulb ◽

Granule Cells ◽

Trpc Channels ◽

Synaptic Activation

Download Full-text

- Proteomic Analysis of TRPC Channels

TRP Channels ◽

10.1201/b10896-10 ◽

2016 ◽

pp. 136-157

Keyword(s):

Proteomic Analysis ◽

Trpc Channels

Download Full-text

Regulation of spinal neuron axon outgrowth by calcium influx through mechanosensitive TrpC channels

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.173.2 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Timothy M Gomez ◽

Bridget Jaques‐Fricke ◽

Patrick Kerstein ◽

Juliana Rengifo ◽

Matt Bobel

Keyword(s):

Calcium Influx ◽

Axon Outgrowth ◽

Spinal Neuron ◽

Trpc Channels

Download Full-text

Dependence of Spontaneous Electrical Activity and Basal Prolactin Release on Nonselective Cation Channels in Pituitary Lactotrophs

Physiological Research ◽

10.33549/physiolres.932301 ◽

2012 ◽

pp. 267-275 ◽

Cited By ~ 4

Author(s):

M. KUČKA ◽

K. KRETSCHMANNOVÁ ◽

S. S. STOJILKOVIC ◽

H. ZEMKOVÁ ◽

M. TOMIĆ

Keyword(s):

Electrical Activity ◽

Action Potentials ◽

Gh3 Cells ◽

Cation Channels ◽

Organic Cations ◽

Trpc Channels ◽

Pituitary Cells ◽

Prolactin Release ◽

Nonselective Cation Channels ◽

Mrna Transcripts

All secretory anterior pituitary cells fire action potentials spontaneously and exhibit a high resting cation conductance, but the channels involved in the background permeability have not been identified. In cultured lactotrophs and immortalized GH3 cells, replacement of extracellular Na+ with large organic cations, but not blockade of voltage-gated Na+ influx, led to an instantaneous hyperpolarization of cell membranes that was associated with a cessation of spontaneous firing. When cells were clamped at –50 mV, which was close to the resting membrane potential in these cells, replacement of bath Na+ with organic cations resulted in an outward-like current, reflecting an inhibition of the inward holding membrane current and indicating loss of a background-depolarizing conductance. Quantitative RT-PCR analysis revealed the high expression of mRNA transcripts for TRPC1 and much lower expression of TRPC6 in both lactotrophs and GH3 cells. Very low expression of TRPC3, TRPC4, and TRPC5 mRNA transcripts were also present in pituitary but not GH3 cells. 2-APB and SKF-96365, relatively selective blockers of TRPC channels, inhibited electrical activity, Ca2+ influx and prolactin release in a concentration-dependent manner. Gd3+, a common Ca2+ channel blocker, and flufenamic acid, an inhibitor of non-selective cation channels, also inhibited electrical activity, Ca2+ influx and prolactin release. These results indicate that nonselective cation channels, presumably belonging to the TRPC family, contribute to the background depolarizing conductance and firing of action potentials with consequent contribution to Ca2+ influx and hormone release in lactotrophs and GH3 cells.

Download Full-text

Abstract 296: Loss of Trpc6 Function in Cardiomyocytes Improves Survival and Attenuates Progression of Cardiac Dysfunction After Mi

Circulation Research ◽

10.1161/res.119.suppl_1.296 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Polina Gross ◽

Xiaoxiao Zhang ◽

Tao Wang ◽

Amir Toib ◽

Markus Wallner ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Dysfunction ◽

Cardiac Myocyte ◽

Transient Receptor Potential ◽

Weight Ratio ◽

Dominant Negative ◽

Heart Weight ◽

Trpc Channels ◽

Pump Function ◽

Hypertrophic Signaling

Ischemic heart disease (IHD) commonly culminates in myocardial infarction (MI), which causes cardiac myocyte death and depressed cardiac pump function. Surviving myocytes can usually maintain pump function by increasing Ca 2+ influx and contractility. However, elevated intracellular Ca 2+ also can activate pathological hypertrophic signaling that promotes cardiac dysfunction and progression into heart failure. Ca 2+ influx through Canonical Transient Receptor Potential (TRPC) channels has been classified as a potential source of hypertrophic signaling. Specifically, TRPC6 gene expression and biological activity is significantly upregulated in cardiac myocytes after MI. Our aim was to determine if TRPC6 loss of function is cardioprotective in MI mouse model. We performed an MI study on cardiac specific dominant negative (dn) TRPC6 transgenic mice that express 3 mutated amino acids (L678A-W680A) in the pore region, which disables TRPC6 channel function. In the course of 6 weeks post MI, dnTRPC6 mice had significantly greater survival (69.2%) than wild-type (WT) mice (47.5%). Cardiac function at 2 weeks post MI was decreased to the same extent in WT and dnTRPC6 mice. Ejection fraction (EF) in WT group was 30.6% vs. 57.1% and in dnTRPC6 EF was 31% vs. 61% (MI vs. sham, respectively). The EF in dnTRPC6 mice 6 weeks post MI suggested attenuation of heart failure progression compared to WT mice (32.5% vs. 26.5%, *P=0.05). Mice in the WT group demonstrated significant elevation in end diastolic and end systolic volumes (EDV and ESV) 6 weeks post MI, while dnTRPC6 had reduced end diastolic and end systolic volumes (116μL vs. 88μL and 106μL vs. 76μL, WT vs. dnTRPC6, EDV and ESV, respectively. ***P<0.0001). Hypertrophy measures of heart weight to body weight ratio and heart weight to tibia length ratio were significantly reduced in dnTRPC6 mice 6 weeks post MI as opposed to WT mice (8.4 vs. 7.3 and 13.4 vs. 11.7, respectively *P<0.05). Hypertrophic markers of ANP, BNP and βMHC followed similar downregulation trend in the dnTRPC6 mice. In conclusion, loss of TRPC6 function slows the progression of cardiac dysfunction and cardiac remodeling in the post MI heart.

Download Full-text

Regulation of Transient Receptor Potential Canonical 4 Activity by Phospholipase C-δ1

10.21203/rs.3.rs-107953/v1 ◽

2020 ◽

Author(s):

Juyeon Ko ◽

Jongyun Myeong ◽

Misun Kwak ◽

Insuk So

Keyword(s):

Phospholipase C ◽

Transient Receptor Potential ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Receptor Potential ◽

Regulation Mechanism ◽

Trpc Channels ◽

Transient Receptor Potential Canonical ◽

Cell Current ◽

Transient Receptor

Abstract Transient receptor potential canonical (TRPC) channels are non-selective calcium-permeable cation channels. It is suggested that TRPC4β and TRPC5 channels are regulated by phospholipase C (PLC) signaling, and are especially maintained by phosphatidylinositol 4,5-bisphosphate (PIP2). The PLCδ subtype is the most Ca2+-sensitive form among the isozymes which cleaves phospholipids to respond to the calcium rise. In this study, we investigated the regulation mechanism of TRPC channel by Ca2+, PLCδ1 and PIP2 signaling cascades. The interaction between TRPC4β and PLCδ1 was identified through the Fӧster resonance energy transfer (FRET) and co-immunoprecipitation (Co-IP). With the electrophysiological experiments, we found that TRPC4β-bound PLCδ1 reduces the overall whole-cell current of channel. The Ca2+-via opened channel promotes the activation of PLCδ1, which subsequently decreases PIP2 level. By comparison TRPC4β activity with or without PLCδ1 using differently [Ca2+]i buffered solution, we demonstrated that PLCδ1 functions in normal condition with physiological calcium range. The negative regulation effect of PLCδ1 on TRPC4β helps to elucidate the roles of each PIP2 binding residues whether they are concerned in channel maintenance or inhibition of channel activity.

Download Full-text