Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that nicotine stimulates cell proliferation of three small-cell lung carcinoma (SCLC) cell lines by activating nicotinic receptors of the neuronal type. Here we report that, in the GLC-8 SCLC cell line, nicotine stimulates mitogen-activated protein (MAP) kinase activity in a concentration- and time-dependent manner (ED50 = 10 nM). The nicotine effect was antagonized by mecamylamine, an antagonist specific for neuronal nicotinic receptors. The absence of extracellular Ca2+, or pretreatment with pertussis toxin or the tyrosine kinase inhibitor genistein inhibited the action of nicotine on MAP kinase. Moreover, supernatants from nicotine-stimulated cells transferred to cells pretreated with mecamylamine were still capable of activating MAP kinase. On the other hand, the same supernatants transferred to cells pretreated with mecamylamine and pertussis toxin or genistein failed to activate MAP kinase. These findings suggest that nicotine elicits its stimulatory effect on MAP kinase in SCLC cells indirectly by inducing the production and/or release of a factor which then acts via a pertussis toxin- and tyrosine kinase-sensitive route.
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PMID:Mechanisms of mitogen-activated protein kinase activation by nicotine in small-cell lung carcinoma cells. 937 7

It has been difficult to observe functional coupling of the D4 receptor to second messenger systems and a robust functional assay system for this receptor is still lacking. In the present study, the rat dopamine D4 receptor was cloned from rat retina. Sequence comparison revealed identity with the published sequence of Ashgari and co-workers, including the two amino acid insertions (V-Q) at position 92 which are not present in the published sequence of O'Malley and coworkers. The rat dopamine D4 receptor was stably expressed in Chinese hamster lung fibroblast CCL39 cells. [3H]spiperone saturation binding yielded a Bmax of 2,370+/-546 fmol/mg protein and a pKD of 8.74+/-0.14 (n=4). Forskolin-stimulated cAMP accumulation was inhibited by dopamine (Emax 61+/-1% inhibition of forskolin-stimulated levels, pEC50 7.33+/-0.06, n=23). A similar concentration-dependent inhibition was observed with the dopamine D2-like receptor agonists quinpirole and 7-OH-DPAT which elicited nearly the same Emax as dopamine. By contrast, apomorphine and a number of compounds with reported affinity for human dopamine D4 receptors (PD168077, U-101958, SDZ GLC 756, L-745,870 and NGD 94-1) behaved as partial agonists (Emax ranging between 26% and 56% of that of dopamine). The agonist effect of dopamine was completely blocked by preincubation with pertussis toxin, no further accumulation of cAMP above the forskolin-stimulated levels being observed. Antagonist pKB-values obtained against dopamine in this system were: 8.55+/-0.19 (n=3) for the partial agonist L-745,870, 8.38+/-0.23 (n=5) for spiperone, 7.18+/-0.17 (n=4) for haloperidol, 7.04+/-0.13 (n=4) for clozapine and <6 for raclopride. Other functional assays applicable were stimulation of [35S]GTPgammaS binding, extracellular acidification rate and a serum-responsive element using luciferase expression as a reporter gene. However, the receptor did not couple to phosphatidylinositol turnover or to intracellular Ca2+. Thus, expression of the rat dopamine D4 receptor in CCL39 cells provided several functional assay systems, of which inhibition of cAMP appeared to be the most robust one. These functional models can be used to evaluate the activity of compounds at the rat dopamine D4 receptor.
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PMID:Cloning, expression, functional coupling and pharmacological characterization of the rat dopamine D4 receptor. 1083 11

Previous studies showed that galanin receptors are expressed in the rat adrenal, and galanin modulates glucocorticoid secretion in this species. Hence, we investigated the expression of the various galanin receptor subtypes (GAL-R1, GAL-R2 and GAL-R3) in the human adrenocortical cells, and the possible involvement of galanin in the control of cortisol secretion. Reverse transcription-polymerase chain reaction detected the expression of GAL-R1 (but not GAL-R2 and GAL-R3) in the inner zones of the human adrenal cortex. The galanin concentration dependently enhanced basal, but not ACTH-stimulated secretion of cortisol from dispersed inner adrenocortical cells (maximal effective concentration, 10(-8) M). The cortisol response to 10(-8) M galanin was abrogated by GAL-R1 immunoneutralization, and unaffected by GAL-R2 or GAL-R3 immunoneutralization. Galanin (10(-8) M) and ACTH (10(-9) M) enhanced cyclic-AMP production from dispersed cells, and the response was suppressed by the adenylate cyclase inhibitor SQ-22536 (10(-4) M). Galanin did not affect inositol triphosphate release, which, in contrast, was raised by angiotensin-II (10(-8) M). SQ-22536 and the protein kinase (PK)A inhibitor H-89 (10(-5) M) abolished the cortisol response to 10(-8) M galanin, while the phospholipase C inhibitor U-73122 and the PKC inhibitor calphostin-C were ineffective. Preincubation with pertussis toxin (Ptx) (0.5 microg/ml) partially inhibited the cortisol response to galanin. We conclude that galanin stimulates cortisol secretion from human inner adrenocortical cells, acting through GAL-R1 coupled to the adenylate cyclase/PKA-dependent signaling cascade via a Ptx-sensitive Galpha protein.
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PMID:Galanin stimulates cortisol secretion from human adrenocortical cells through the activation of galanin receptor subtype 1 coupled to the adenylate cyclase-dependent signaling cascade. 1798 95