Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.4.3 (
phospholipase C
)
18,461
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Dysfunction of the
tubby
protein results in maturity-onset obesity in mice. Tubby has been implicated as a transcription regulator, but details of the molecular mechanism underlying its function remain unclear. Here we show that
tubby
functions in signal transduction from heterotrimeric GTP-binding protein (G protein)-coupled receptors. Tubby localizes to the plasma membrane by binding phosphatidylinositol 4,5-bisphosphate through its carboxyl terminal "tubby domain." X-ray crystallography reveals the atomic-level basis of this interaction and implicates
tubby
domains as phosphorylated-phosphatidyl- inositol binding factors. Receptor-mediated activation of G protein alphaq (Galphaq) releases
tubby
from the plasma membrane through the action of
phospholipase C
-beta, triggering translocation of
tubby
to the cell nucleus. The localization of
tubby
-like protein 3 (TULP3) is similarly regulated. These data suggest that
tubby
proteins function as membrane-bound transcription regulators that translocate to the nucleus in response to phosphoinositide hydrolysis, providing a direct link between G-protein signaling and the regulation of gene expression.
...
PMID:G-protein signaling through tubby proteins. 1140 44
M-channels are voltage-gated K+ channels that regulate the excitability of many neurons. They are composed of Kv7 (KCNQ) family subunits, usually Kv7.2 + Kv7.3. Native M-channels and expressed Kv7.2 + 7.3 channels are inhibited by stimulating G(q/11)-coupled receptors - prototypically the M1 muscarinic acetylcholine receptor (M1-mAChR). The channels require membrane phosphatidylinositol-4,5-bisphosphate (PIP(2)) to open and the effects of mAChR stimulation result primarily from the reduction in membrane PIP(2) levels following G(q)/
phospholipase C
-catalysed PIP(2) hydrolysis. However, in sympathetic neurons, M-current inhibition by bradykinin appears to be mediated through the release and action of intracellular Ca(2)+ by inositol-1,4,5-trisphosphate (IP(3)), a product of PIP(2) hydrolysis, rather than by PIP(2) depletion. We have therefore compared the effects of bradykinin and oxotremorine-M (a muscarinic agonist) on membrane PIP(2) in sympathetic neurons using a fluorescently tagged mutated C-domain of the PIP(2) binding probe, '
tubby
'. In concentrations producing equal M-current inhibition, bradykinin produced about one-quarter of the reduction in PIP(2) produced by oxotremorine-M, but equal reduction when PIP(2) synthesis was blocked with wortmannin. Likewise, wortmannin restored bradykinin-induced M-current inhibition when Ca(2)+ release was prevented with thapsigargin. Thus, inhibition by bradykinin can use product (IP(3)/Ca(2)+)-dependent or substrate (PIP(2)) dependent mechanisms, depending on Ca(2)+ availability and PIP(2) synthesis rates.
...
PMID:Regulation of M(Kv7.2/7.3) channels in neurons by PIP(2) and products of PIP(2) hydrolysis: significance for receptor-mediated inhibition. 1739 26
Inward rectifier K
+
channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP
2
). Stimulation of the Ca
2+
-sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both G
q/11
, which decreases PIP
2
, and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP
2
. How membrane PIP
2
levels are regulated by CaR activation and whether these changes modulate inward rectifier K
+
are unknown. In this study, we found that activation of CaR by the allosteric agonist, NPSR568, increased inward rectifier K
+
current (I
K1
) in guinea pig ventricular myocytes and currents mediated by Kir2.1 channels exogenously expressed in HEK293T cells with a similar sensitivity. Moreover, using the fluorescent PIP
2
reporter
tubby
-R332H-cYFP to monitor PIP
2
levels, we found that CaR activation in HEK293T cells increased membrane PIP
2
concentrations. Pharmacological studies showed that both
phospholipase C
(
PLC
) and PI-4-K are activated by CaR stimulation with the latter played a dominant role in regulating membrane PIP
2
and, thus, Kir currents. These results provide the first direct evidence that CaR activation upregulates currents through inward rectifier K
+
channels by accelerating PIP
2
synthesis. The regulation of I
K1
plays a critical role in the stability of the electrical properties of many excitable cells, including cardiac myocytes and neurons. Further, synthetic allosteric modulators that increase CaR activity have been used to treat hyperparathyroidism, and negative CaR modulators are of potential importance in the treatment of osteoporosis. Thus, our results provide further insight into the roles played by CaR in the cardiovascular system and are potentially valuable for heart disease treatment and drug safety.
...
PMID:Activation of the Ca
2+
-sensing receptors increases currents through inward rectifier K
+
channels via activation of phosphatidylinositol 4-kinase. 2783 49
