AJP - Endocrinology and Metabolism, Vol 252, Issue 6 E783-E789, Copyright © 1987 by American Physiological Society
Multiple effects of phorbol esters on hormone-sensitive adenylate cyclase activity in S49 lymphoma cells
J. D. Bell and L. L. Brunton
In S49 lymphoma cells, 12-O-tetradecanoyl phorbol-13-acetate (TPA) enhances
adenylate cyclase activity and doubles cAMP accumulation in response to
beta-adrenergic stimulation at 37 degrees C, putatively via the action of
protein kinase C. At 27 degrees C, TPA has the opposite effect, inhibiting
cAMP production in response to isoproterenol by approximately 25%. TPA also
inhibits the response to prostaglandin E1 (PGE1), another stimulant of
hormone-sensitive adenylate cyclase in these cells, by 30% at 37 degrees C
and almost 50% at 27 degrees C. In contrast, TPA enhances responses to
forskolin and cholera toxin at both 27 and 37 degrees C. In membranes from
cells treated with TPA, PGE1-stimulated adenylate cyclase activity is
inhibited by 50%, whereas the catalytic activity stimulated by NaF or
forskolin is enhanced. TPA reduces the potency of both PGE1 and
isoproterenol for cAMP generation by 50%. TPA causes a similar decrease in
beta-adrenergic agonist affinity with no reduction in the density of either
antagonist or agonist binding sites in wild type cells and in cells lacking
the alpha-subunit of the stimulatory transducer protein (Gs) (cyc-) or
lacking functional receptor Gs coupling (UNC). Therefore, TPA has at least
three functionally distinct effects on hormone-sensitive adenylate cyclase
in S49 cells: a 50% reduction in agonist affinity, attenuation of
receptor-transducer coupling, and enhancement of GTP-dependent catalytic
activity. We conclude that multiple and opposing effects of TPA on
hormone-sensitive adenylate cyclase occur simultaneously within the same
cell, affecting the responses to several agonists differently.(ABSTRACT
TRUNCATED AT 250 WORDS)
