Fluoroaluminates mimic muscarinic- and oxytocin-receptor-mediated generation of inositol phosphates and contraction in the intact guinea-pig myometrium. Role for a pertussis/cholera-toxin-insensitive G protein.

Oct 15, 1988The Biochemical journal

Fluoroaluminates mimic hormone receptor signals that produce cell messengers and cause contractions in guinea pig uterine muscle, involving a special G protein unaffected by common toxins

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Abstract

Carbachol and oxytocin stimulated a specific receptor-mediated phospholipase C activation in the intact guinea-pig myometrium.

Stimulation with carbachol and oxytocin resulted in the breakdown of a specific lipid, leading to the production of inositol phosphates.
NaF plus AlCl3 induced a dose-dependent generation of inositol phosphates and uterine contractions, suggesting an active species involved.
The inositol phosphate generation and uterine contractions triggered by carbachol and oxytocin were not affected by pertussis toxin.
Cholera toxin did not influence the basal or oxytocin-induced generation of inositol phosphates but slightly reduced the response to muscarinic stimulation.
Evidence indicates that a distinct G protein mediates the activity of muscarinic and oxytocin receptors in the myometrium, separate from those involved in cyclic AMP signaling.

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1. In the intact guinea-pig myometrium, carbachol and oxytocin stimulated a specific receptor-mediated phospholipase C activation, catalysing the breakdown of PtdIns(4,5)P2 with the sequential generation of InsP3, InsP2 and InsP. Stimulation of muscarinic receptors also triggered an inhibition of cyclic AMP accumulation caused by prostacyclin. 2. NaF plus AlCl3 mimicked the effects of carbachol and oxytocin by inducing, in a dose-dependent manner, the generation of all three inositol phosphates as well as uterine contractions. AlCl3 enhanced the fluoride effect, supporting the concept that A1F4- was the active species. Under similar conditions, fluoroaluminates activated the guanine nucleotide regulatory protein Gi, reproducing the inhibitory effect of carbachol on cyclic AMP concentrations. 3. Both carbachol- and oxytocin-mediated increases in inositol phosphates, as well as contractions, were insensitive to pertussis toxin, under conditions where the expression of Gi was totally prevented. Cholera toxin, which activates Gs and enhances cyclic AMP accumulation, failed to affect basal or oxytocin-evoked inositol phosphate generation, but induced a slight, though consistent, attenuation of the muscarinic inositol phosphate response, which was similarly evoked by forskolin. 4. The data provide evidence that, in the myometrium, (a) a G protein mediates the generation of inositol phosphates and the Ca2+-dependent contractile event, (b) the relevant G protein that most probably couples muscarinic and oxytocin receptors to phospholipase C is different from Gi and Gs, the proteins that couple receptors to adenylate cyclase, and (c) cyclic AMP does not seem to control the phosphoinositide cycle, but rather exerts a negative regulation at the muscarinic-receptor level.

Fluoroaluminates mimic muscarinic- and oxytocin-receptor-mediated generation of inositol phosphates and contraction in the intact guinea-pig myometrium. Role for a pertussis/cholera-toxin-insensitive G protein.

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