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Phorbol Esters Increase GTP‐Dependent Adenylate Cyclase Activity in Rat Brain Striatal Membranes
Author(s) -
Olianas Maria C.,
Onali Pierluigi
Publication year - 1986
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1986.tb00694.x
Subject(s) - gtp' , adenylate kinase , cyclase , forskolin , chemistry , phorbol , cholera toxin , stimulation , biochemistry , protein kinase c , medicine , endocrinology , enzyme , biology , receptor
4β‐Phorbol 12‐myristate 13‐acetate (PMA), added to a lysed mitochondrial fraction of rat striatum, stimulates adenylate cyclase activity with an apparent time lag of ∼30 s. Half‐maximal and maximal enzyme stimulations are obtained with 8 and 200 n M PMA, respectively. The PMA stimulation is GTP dependent, reaching a maximum of ∼60% at 50 μ .M GTP, and is associated with disappearance of the enzyme inhibition induced by micromolar concentrations of GTP. Enhancement of enzyme activity by cholera toxin and 3,4‐dihydroxyphenylethylamine is amplified by PMA only at micromolar concentrations of GTP. PMA does not affect the enzyme stimulation by forskolin but reverses the inhibition of forskolin‐stimulated enzyme by GTP. When guanyl‐5′‐yl‐imidodiphosphate is substituted for GTP, PMA does not modify adenylate cyclase activity. Enzyme inhibition by acetylcholine, Leu‐enkephalin, and R (‐) N 6 ‐(2‐phenylisopropyl)adenosine is magnified by PMA. Stimulation of adenylate cyclase by PMA is markedly reduced following EGTA treatment, is not observed when adenyl‐5′‐yl‐imidodiphosphate is substituted for ATP as substrate for adenylate cyclase, and is enhanced by l‐α‐phosphatidyl‐l‐serine. Like PMA, 4β‐phorbol 12,13‐dibutyrate and 1‐oleoyl‐2‐acetylglycerol stimulate striatal adenylate cyclase, whereas 4β‐phorbol and 4β‐phorbol 13‐acetate are ineffective. The results indicate that phorbol esters increase striatal adenylate cyclase activity by reducing the GTP‐induced inhibition of the enzyme, presumably as a result of protein kinase C activation.