Signaling pathways involved in myometrial inhibition by CGRP

Myometrial contractility changes continuously to support the reproductive function of the uterus. Deciphering the stimulatory and inhibitory signaling pathways that mediate this functional adaptability is of great importance for controlling pathological situations, such as premature labor or dystocia.Calcitonin Gene Related Peptide (CGRP) is a potent uterine relaxant, delivered to the myometrium by afferent sensitive fibers. The present study explores the involvement of Ca2+ homeostasis mechanisms in the transduction pathways of CGRP in myometrium. Simultaneous assessments of isometric force, [Ca2+]i or [cAMP] at different stages of contractions reveal at least two signaling pathways for CGRP. Applied prior to excitation, CGRP diminishes Ca2+ accumulation and consequently decreases the force developed during depolarization- and agonist-induced contractions. The other pathway is a [Ca2+]i-independent reduction of contractility, revealed by the CGRP relaxation of K+ precontracted muscles.Forskolin can mimic both the Ca2+-dependent and Ca 2+-independent reductions of myometrial contractility by CGRP. Furthermore, a phosphodiesterase inhibitor augments the anti-contracting effects of CGRP. These results suggest that both Ca2+-dependent and C 2+-independent pathways of CGRP signaling are mediated by enhancement of cAMP production.The cause of the inhibition of [Ca2+]i transients is a reduced release of C2+ from depolarization- and IP3-sensitive pools, as indicated by experiments performed in the absence of extracellular Ca2+. When the contribution of the internal stores of Ca 2+ is eliminated, CGRP does not reduce the calcium transients, suggesting that CGRP signaling does not affect Ca2+ entry. It also appears that the Ca2+ removal mechanisms are not accelerated.Prolonged exposure to CGRP elicits slow, but statistically significant rises of resting [Ca2+]i. A theoretically possible scenario whereby depletion of SR by the slow release of Ca2+ would fully account for the diminution in the SR participation in contraction is not confirmed statistically. The functional significance of the slow Ca 2+ release, like BK channels activation by CGRP in a resting or agonist-contracted muscle or activation of PKC, are discussed.Thus, CGRP can inhibit contraction of myometrial smooth muscle at different stages of the excitation-contraction coupling, making this an efficient control mechanism for uterine contractility, a natural relaxant possibly released in response to myometrial stretch