Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphorylation of Ser19 on the 20-kDa regulatory light chain of myosin II (MLC20) by Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK) is essential for initiation of smooth muscle contraction. The initial [Ca2+]i transient is rapidly dissipated and MLCK inactivated, whereas MLC20 and muscle contraction are well maintained. Sustained contraction does not reflect Ca2+ sensitization because complete inhibition of MLC phosphatase activity in the absence of Ca2+ induces smooth muscle contraction. This contraction is suppressed by staurosporine, implying participation of a Ca2+-independent MLCK. Thus, sustained contraction, as with agonist-induced contraction at experimentally fixed Ca2+ concentrations, involves (a) G protein activation, (b) regulated inhibition of MLC phosphatase, and (c) MLC20 phosphorylation via a Ca2+-independent MLCK. The pathways that lead to inhibition of MLC phosphatase by G(q/13)-coupled receptors are initiated by sequential activation of Galpha(q)/alpha13, RhoGEF, and RhoA, and involve Rho kinase-mediated phosphorylation of the regulatory subunit of MLC phosphatase (MYPT1) and/or PKC-mediated phosphorylation of CPI-17, an endogenous inhibitor of MLC phosphatase. Sustained MLC20 phosphorylation is probably induced by the Ca2+-independent MLCK, ZIP kinase. The pathways initiated by G(i)-coupled receptors involve sequential activation of Gbetagamma(i), PI 3-kinase, and the Ca2+-independent MLCK, integrin-linked kinase. The last phosphorylates MLC20 directly and inhibits MLC phosphatase by phosphorylating CPI-17. PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC2 and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities. These kinases also act downstream to inhibit (a) initial contraction by inhibiting Ca2+ mobilization and (b) sustained contraction by inhibiting RhoA and targets downstream of RhoA. This increases MLC phosphatase activity and induces MLC20 dephosphorylation and muscle relaxation.
 ...
PMID:Signaling for contraction and relaxation in smooth muscle of the gut. 1646 Feb 76

Vasoactive intestinal peptide (VIP) relaxes smooth muscle by interacting with receptors coupled to cAMP- or cGMP-signalling pathways. Their relative contribution to human gastric relaxation is unknown. This study aimed at investigating, in terms of biological activity, receptor expression and related signalling pathways, the action of VIP separately on the human fundus and the antrum. VIP caused greater relaxation of smooth muscle cells (SMC) and strips of the antrum presenting on the former a higher efficacy and potency (ED(50): 0.53 +/- 0.17 nmol L(-1)) than on the fundus (ED(50): 3.4 +/- 1.4 nmol L(-1)). On both fundus and antrum strips, its effect was tetrodotoxin insentitive. Reverse transcriptase-polymerase chain reaction analysis showed the sole expression of VPAC2 and natriuretic peptide clearance receptors, with VPAC2 being more abundant in the antrum. Functional regional differences in receptor-related signalling pathways were found. Activation of the cAMP-pathway by forskolin or its inhibition by adenylate cyclase (2'5'-dideoxyadenosine) or kinase (Rp-cAMPs) inhibitors had more pronounced effects on antrum SMC. Activation of the cGMP-pathway by sodium nitroprusside or its inhibition by guanylate cyclase (LY83583) or kinase (KT5823) inhibitors had more effects on fundus SMC, on which a higher expression of endothelial nitric oxide synthase was found. In conclusion, regional differences in VIP action on human stomach are related to distinct myogenic properties of SMC of the antrum and the fundus.
 ...
PMID:Vasoactive intestinal peptide receptor subtypes and signalling pathways involved in relaxation of human stomach. 1704 Apr 12