Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gonadotropin-releasing hormone (GnRH) secretion is modulated by a large number of neuromediators, among which catecholamines play a central role. Previous results have shown that both dopamine (DA) and norepinephrine (NE) stimulate GnRH secretion in GT1 neuronal cell lines. These stimulatory effects appear to involve D1-dopaminergic and beta 1-adrenergic receptors positively coupled to adenylate cyclase. However, in spite of a similar efficacy of these catecholamines to stimulate GnRH secretion, DA is two-fold more efficacious than NE to stimulate the formation of cyclic AMP. This rises the possibility that other signaling pathways and other receptor subtypes could be involved in the catecholaminergic stimulation of GnRH release. Since the signaling pathway triggered by phosphoinositide hydrolysis is a potent stimulator of GnRH secretion and appears to mediate the releasing actions of neuromediators such as histamine and endothelin, we investigated if this signaling pathway was also involved in the catecholaminergic stimulation of GnRH release in GT1 cells. Both DA and NE stimulated inositol phosphates production in GT1-1 cells with a very low potency and long latency with respect to GnRH secretion. Inositol phosphates production was stimulated by DA and NE only at a concentration of 100 microM, i.e. two to three orders of magnitude higher than the effective concentrations to maximally stimulate GnRH secretion. The effects of both catecholamines do not appear to be secondary to the stimulation of cyclic AMP production, since treatment of GT1-1 cells with forskolin did not affect inositol phosphates production. The effects of DA and NE on inositol phosphates production were blocked by specific antagonists such as SCH-23390, spiroperidol and phentolamine. However, specific dopaminergic agonists such as SKF-38393 and bromocriptine, or adrenergic agonists such as clonidine, methoxamine and isoproterenol were not capable of stimulating inositol phosphates production. Thus, due to the low potency and apparent non-specificity of these effects, we conclude that inositol phosphates production is not involved in the catecholaminergic stimulation of GnRH release.
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PMID:The catecholaminergic stimulation of gonadotropin-releasing hormone release by GT1-1 cells does not involve phosphoinositide hydrolysis. 862 71

NKH-477 is a water-soluble analogue of forskolin that stimulates adenylate cyclase and has antidepressant properties in the forced swim model of depression. The effect of chronic NKH-477 on locomotion and rearing and its behavioural interaction with lithium and inositol was tested. NKH-477 (1.5 mg/kg), administered acutely or chronically for 9 d to rats, induced a significant reduction in locomotor behaviour and rearing. In a second experiment, rats were pretreated with chronic dietary lithium, inositol or control diet for 3 wk before being injected with either saline or NKH-477. Inositol had no effect on the decreased locomotion and rearing induced by NKH-477. There was a significant, but transient, interaction between lithium and NKH-477 on rearing on the second and third days of treatment. The lithium group had lower baseline rearing than control or inositol-treated rats, and was not further affected by NKH-477 treatment. This is the first report of a marked effect of this forskolin analogue on locomotion and rearing, with no tolerance in the time frame examined. The interaction between NKH-477 and lithium suggests that the well-documented ability of lithium to inhibit stimulation of the cAMP system is relevant to its behavioural effects; however, the transient nature of this interaction, suggests that other biochemical mechanisms are involved in the behavioural effects of lithium.
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PMID:Behavioural effects of NKH-477, a forskolin analogue, on locomotion and rearing in rats. 1134 75


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