Activation of TRPC6 channels promotes endocannabinoid biosynthesis in neuronal CAD cells

Bardell, Tamera K.; Barker, Eric L.

doi:10.1016/j.neuint.2010.05.002

Cited by 11 publications

(14 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immunogold labeling of isolated phagosomal membrane fragments from (R)-roscovitine-treated cells using α-hTRPC6 796-809 demonstrated significant TRPC6 localization over that seen in the control membranes (Fig. 6 B, 2), indicating clustering and possible targeting to membrane lipid rafts as has been reported for a number of TRP channels (27)(28)(29)(30)(31). Recent data demonstrate that hypoxia induces TRPC6 translocation to caveolin-and sphingolipid-rich membrane rafts in human pulmonary artery smooth-muscle cells (32).…”

Section: Translocation Of Trpc6 To the Plasma Membrane Upon Exposure supporting

confidence: 53%

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Riazanski

Gabdoulkhakova

Boynton

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Defects in the innate immune system in the lung with attendant bacterial infections contribute to lung tissue damage, respiratory insufficiency, and ultimately death in the pathogenesis of cystic fibrosis (CF). Professional phagocytes, including alveolar macrophages (AMs), have specialized pathways that ensure efficient killing of pathogens in phagosomes. Phagosomal acidification facilitates the optimal functioning of degradative enzymes, ultimately contributing to bacterial killing. Generation of low organellar pH is primarily driven by the V-ATPases, proton pumps that use cytoplasmic ATP to load H+ into the organelle. Critical to phagosomal acidification are various channels derived from the plasma membrane, including the anion channel cystic fibrosis transmembrane conductance regulator, which shunt the transmembrane potential generated by movement of protons. Here we show that the transient receptor potential canonical-6 (TRPC6) calcium-permeable channel in the AM also functions to shunt the transmembrane potential generated by proton pumping and is capable of restoring microbicidal function to compromised AMs in CF and enhancement of function in non-CF cells. TRPC6 channel activity is enhanced via translocation to the cell surface (and then ultimately to the phagosome during phagocytosis) in response to G-protein signaling activated by the small molecule (R)-roscovitine and its derivatives. These data show that enhancing vesicular insertion of the TRPC6 channel to the plasma membrane may represent a general mechanism for restoring phagosome activity in conditions, where it is lost or impaired.

show abstract

Section: Translocation Of Trpc6 To the Plasma Membrane Upon Exposure supporting

confidence: 53%

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Riazanski

Gabdoulkhakova

Boynton

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Many signal molecules accumulate in the caveolae, including caveolin-1, tyrosine kinase, Raf, MEK1/2 and TRPC6. 10,11 Caveolae is, therefore, deemed to play an important role in cell growth.…”

Section: Introductionmentioning

confidence: 99%

Effects of caveolin-1 and P-ERK1/2 on Ang II-induced glomerular mesangial cell proliferation

Zhang

2013

Renal Failure

View full text Add to dashboard Cite

This study explored the effects of caveolin-1, p-ERK1/2 and transient receptor potential channel 6 (TRPC6) on angiotensin II (Ang II)-induced glomerular mesangial cell (GMC) proliferation, and investigated the role of Ang II on GMC proliferation. GMC cultures were divided into Control, Ang II (Ang II 10 À7 mol/L), PD98059 (Ang II 10 À7 mol/L þ PD98059 5 Â 10 À5 mol/L) and MbCD groups (Ang II 10 À7 mol/L þ MbCD 10 À2 mol/L). GMCs proliferation was measured by the methyl thiazolil tetracolium and trypan blue assays. The distribution of caveolin-1, p-ERK1/2 and TRPC6 was monitored by immunocytochemistry. Real time polymerase chain reaction (PCR) was used to assess mRNA expression of caveolin-1 and TRPC6. Western blot analysis was used to assess protein expression of caveolin-1, p-ERK1/2 and TRPC6. The results showed that Ang II promoted GMC proliferation. PD98059 and MbCD blocked Ang II-induced GMC proliferation, by 31.06% and 48.96%, respectively. In comparison with the control group, the expression of p-ERK1/2 and TRPC6 was significantly higher and caveolin-1 expression was significantly lower in the Ang II group. PD98059 markedly decreased p-ERK1/2 and TRPC6 expression and increased caveolin-1 expression. MbCD decreased the expression of p-ERK1/2 and TRPC6, but had no significant effect on caveolin-1 protein expression. These findings suggested that the intact caveolae structure was associated with Ang II-induced GMC proliferation, ERK1/2 activation and TRPC6 expression. And p-ERK1/2 acted as an upstream signal molecule for TRPC6. Moreover, p-ERK1/2 and caveolin-1 appeared to be inhibited reciprocally, thus regulated GMC proliferation by regulating TRPC6 expression.

show abstract

“…These non-selective cation channels are involved in a diverse range of regulatory mechanisms including thermoregulation, olfaction, osmoregulation, pressure and acid sensation, stretch-evoked responses and many more (Clapham, 2007, Desai and Clapham, 2005, Clapham et al, 2001, Di Marzo and De Petrocellis, 2010, Venkatachalam and Montell, 2007. Few TRP channel endogenous ligands have been identified but the result of TRP channel activation is cell depolarisation and Ca 2+ influx (Wu et al, 2010, Bardell andBarker, 2010). Many TRP channels are potentiated by intracellular phospholipase C activation and also by activation of G protein-coupled receptors and tyrosine kinase receptors (Wu et al, 2010, Clapham et al, 2001.…”

Section: +mentioning

confidence: 99%

“…Many TRP channels are potentiated by intracellular phospholipase C activation and also by activation of G protein-coupled receptors and tyrosine kinase receptors (Wu et al, 2010, Clapham et al, 2001. Additionally, elevations in intracellular Ca 2+ modulates almost all TRP channels (Wu et al, 2010, Bardell andBarker, 2010). Evidence of direct activation of a TRP channel (TRPM3) by an endogenous neurosteroid pregnenalone sulphate was shown in pancreatic β cells (Wagner et al, 2008, Nilius andVoets, 2008).…”

Section: +mentioning

confidence: 99%

“…The synthesis of endocannabinoids anandamide and 2-arachidonoyl glycerol (2-AG) is triggered by an increase in cytoplasmic Ca 2+ (Wilson and Nicoll, 2001, Bardell and Barker, 2010, Kreitzer and Regehr, 2002 and depolarisation-dependent release from neurons (Pertwee, 1999. The resultant endogenously synthesised cannabinoids then function as neuromodulators or neurotransmitters (Pertwee, 1999, Alger, 2002, Lozovaya et al, 2011, Wilson and Nicoll, 2001).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The safety, efficacy and neuromotor effects of the neurosteroid anaesthetic alfaxalone in rats

Lau¹

View full text Add to dashboard Cite

Rodents are routinely anaesthetised for husbandry and biomedical research purposes. All anaesthetics carry a degree of risk, complications and side effects. An ideal anaesthetic for rodents is safe, predictable, alleviates pain and distress and can be performed without specialist training. A survey was created to identify anaesthetic agents frequently administered to rodents currently utilised by the research community. Findings indicated injectable anaesthetics were very commonly used and complications were often associated with use, highlighting the lack of a safe, predictable laboratory rodent anaesthetic protocol.Alfaxalone is a neuroactive steroid injectable anaesthetic agent with a high margin of safety, and is commonly used in veterinary anaesthesia as the Alfaxan® formulation. I sought to establish whether alfaxalone could be used as an injectable anaesthetic agent for laboratory rodents. A plasma pharmacokinetics study was performed using IV and IP Alfaxan® in adult female Wistar rats (7-10 weeks). Mean T 1/2elim for 2 and 5 mg.kg -1 IV was short (~17 minutes), but could not be estimated for IP dosing due to sustained plasma levels for up to 60 minutes after injection. Cl p for IV injection was calculated at 24.5% and 23% of cardiac output respectively. The observed C max was 2.99 mg.L -1 for IP administration, and 2.2 ± 0.9 and 5.2 ± 1.3 mg.L -1 for 2 and 5 mg.kg -1 IV administration respectively. AUC 0-60 was 96 min.mg.L -1 for IP dosing. The relative bioavailability for IP dosing was 26% and 28%, compared to IV doses of 2 and 5mg.kg -1 respectively. Alfaxalone given IP caused longer sleep times than IV dosing, although anaesthesia was not induced in 30% of rats.Importantly, all rats exhibited muscle twitching after alfaxalone administration. I then sought to test whether combining IP injection of Alfaxalone with common premedication agents could improve anaesthetic induction rates and reduce muscle twitching, to provide a viable anaesthetic regimen for rats. Medetomidine (0.5 mg.kg -1 ), medetomidine-butorphanol (0.35 mg.kg -1 -0.2 mg.kg -1 ), Acetylpromazine (ACP) -methadone (3 mg.kg -1 -0.7 mg.kg -1 ) and ACP-xylazine (3 mg.kg -1 -3 mg.kg -1 )were administered IP 10 minutes prior to IP alfaxalone (20 mg.kg -1 ). ACP-xylazine, medetomidine and medetomidine-butorphanol all significantly reduced twitching. Medetomidine-butorphanol provided surgical anaesthesia without prolonged recovery and provided an adequate plane of anaesthesia for short painful surgical procedures.However, none of these premedication agents fully eliminated alfaxalone-induced muscle twitching. I therefore carried out electrophysiological studies of motor neurons (MN), to determine the mechanism causing neuromotor excitation in response to alfaxalone. Previous data has shown that alfaxalone can modulate strychnine-sensitive glycinergic receptors, which may, in part, contribute to the adverse neuromotor excitatory responses manifested as muscle twitching during alfaxalone anaesthesia. The 3 effects of alfaxalone on inhibito...

show abstract

Activation of TRPC6 channels promotes endocannabinoid biosynthesis in neuronal CAD cells

Cited by 11 publications

References 67 publications

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

Effects of caveolin-1 and P-ERK1/2 on Ang II-induced glomerular mesangial cell proliferation

The safety, efficacy and neuromotor effects of the neurosteroid anaesthetic alfaxalone in rats

Contact Info

Product

Resources

About