Dataset Information

Dissection of the components for PIP2 activation and thermosensation in TRP channels.

ABSTRACT: Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a central role in the activation of several transient receptor potential (TRP) channels. The role of PIP2 on temperature gating of thermoTRP channels has not been explored in detail, and the process of temperature activation is largely unexplained. In this work, we have exchanged different segments of the C-terminal region between cold-sensitive (TRPM8) and heat-sensitive (TRPV1) channels, trying to understand the role of the segment in PIP2 and temperature activation. A chimera in which the proximal part of the C-terminal of TRPV1 replaces an equivalent section of TRPM8 C-terminal is activated by PIP2 and confers the phenotype of heat activation. PIP2, but not temperature sensitivity, disappears when positively charged residues contained in the exchanged region are neutralized. Shortening the exchanged segment to a length of 11 aa produces voltage-dependent and temperature-insensitive channels. Our findings suggest the existence of different activation domains for temperature, PIP2, and voltage. We provide an interpretation for channel-PIP2 interaction using a full-atom molecular model of TRPV1 and PIP2 docking analysis.

SUBMITTER: Brauchi S

PROVIDER: S-EPMC1891241 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Dissection of the components for PIP2 activation and thermosensation in TRP channels.

Brauchi Sebastian S Orta Gerardo G Mascayano Carolina C Salazar Marcelo M Raddatz Natalia N Urbina Hector H Rosenmann Eduardo E Gonzalez-Nilo Fernando F Latorre Ramon R

Proceedings of the National Academy of Sciences of the United States of America 20070604 24

Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a central role in the activation of several transient receptor potential (TRP) channels. The role of PIP2 on temperature gating of thermoTRP channels has not been explored in detail, and the process of temperature activation is largely unexplained. In this work, we have exchanged different segments of the C-terminal region between cold-sensitive (TRPM8) and heat-sensitive (TRPV1) channels, trying to understand the role of the segment in PIP2 and ...[more]

PMID: 17548815

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Project description:Kisspeptin signaling via its Gαq-coupled receptor GPR54 plays a crucial role in modulating GnRH neuronal excitability, which controls pituitary gonadotropins secretion and ultimately reproduction. Kisspeptin potently depolarizes GnRH neurons primarily through the activation of canonical transient receptor potential (TRPC) channels, but the intracellular signaling cascade has not been elucidated. Presently, we have established that kisspeptin activation of TRPC channels requires multiple membrane and intracellular signaling molecules. First, phosphatidylinositol-4,5-bisphosphate (PIP(2)) hydrolysis by phospholipase Cβ is required because whole-cell dialysis of Dioctanoylglycerol-PIP(2) (DiC8-PIP(2)) inhibited the kisspeptin activation of TRPC channels, and the phosphatidylinositol 4-kinase inhibitor wortmannin, which attenuates PIP(2) synthesis, prolonged TRPC channel activation. Using single cell RT-PCR, we identified that the mRNA for the PIP(2)-interacting TRPC channel subunit, TRPC4α, is expressed in GnRH neurons. Depletion of intracellular Ca(2+) stores by thapsigargin and inositol 1,4,5-trisphosphate had no effect, indicating that the TRPC channels are not store-operated. Neither removing extracellular Ca(2+) nor buffering intracellular Ca(2+) with EGTA or BAPTA had any effect on the kisspeptin activation of the TRPC channels. However, the Ca(2+) channel blocker Ni(2+) inhibited the kisspeptin-induced inward current. Moreover, inhibition of protein kinase C by bisindolylmaleimide-I or calphostin C had no effect, but activation of protein kinase C by phorbol 12,13-dibutyrate occluded the kisspeptin-activated current. Finally, inhibition of the cytoplasmic tyrosine kinase cSrc by genistein or the pyrazolo-pyrimidine PP2 blocked the activation of TRPC channels by kisspeptin. Therefore, TRPC channels in GnRH neurons are receptor-operated, and kisspeptin activates TRPC channels through PIP(2) depletion and cSrc tyrosine kinase activation, which is a novel signaling pathway for peptidergic excitation of GnRH neurons.

Dataset Information

Dissection of the components for PIP2 activation and thermosensation in TRP channels.

Publications

Dissection of the components for PIP2 activation and thermosensation in TRP channels.

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