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Regulation of adenylate cyclase activity in hamster adipocytes

Inhibition by prostaglandins, α-adrenergic agonists and nicotinic acid

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Summary

In ghosts of hamster adipocytes, the regulation of adenylate cyclase (ATP: pyrophosphate lyase, cyclizing; EC 4.6.1.1) activity by prostaglandins, α-adrenergic agonists and nicotinic acid was studied. These three classes of antilipolytic agents caused adenylate cyclase inhibition without an apparent lag phase. Maximal inhibitions observed ranged between about 45% (by α-adrenergic agonists) and 60% (by prostaglandins and nicotinic acid). The order of potency for the inhibitory prostaglandins (PG) was PGE1 ≧ PGE2>PGF2α≅PGI2>PGD2>6-keto PGF1α. The IC50 values obtained were about 0.007, 0.06, 0.3 and 1 μM for PGE1, PGF2α, PGD2 and 6-keto PGF1α, respectively. α-Adrenergic agonists, studied in the presence of the β-adrenergic blocking agent, propranolol (30 μM), inhibited the fat cell enzyme with the order of potency (1)-adrenaline > (1)-α-methylnoradrenaline ≅ (1)-noradrenaline > clonidine ≅ tetryzoline > (1)-phenylephrine. The IC50 values obtained for (1)-adrenaline and (1)-noradrenaline were about 3 and 10 μM, respectively. The inhibitory effect of (1)-adrenaline was blocked by the α-adrenergic antagonists with the potency order yohimbine ≅ phentolamine > prazosin. These findings suggest that an α2 of receptors is involved in this catecholamine-induced inhibition. Nicotinic acid (10 μM) reduced adenylate cyclase activity by about 60% with half-maximal effectiveness at about 0.6 μM. The nicotinic acid derivatives, nicotinamide, β-pyridylcarbinol and NAD (up to 100 μM), had no effect on enzyme activity.

Inhibition of the hamster adipocyte adenylate cyclase by the antilipolytic agents required the presence of both GTP, which reduced “basal” activity by about 80% at 10 μM, and sodium ions, which specifically activated the GTP-affected from of the enzyme. Inhibition was also observed in the presence of ACTH, which in a GTP-dependent manner increased adenylate cyclase activity. Pretreatment of the enzyme preparation with NaF (10 mM) partially reduced the inhibitory effect, and preactivation with the stable GTP analogue, guanylyl 5′-imidodiphosphate (100 μM), abolished the adenylate cyclase inhibition by the antilipolytic agents.

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Abbreviations

PG:

prostaglandin

GMP-P(NH)P:

guanylyl 5′-imidodiphosphate

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Authors and Affiliations

  1. Pharmakologisches Institut der Universität Heidelberg, Im Neuenheimer Feld 366, D-6900, Heidelberg, Federal Republic of Germany

    Klaus Aktories, Günter Schultz & Karl H. Jakobs

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  1. Klaus Aktories
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  2. Günter Schultz
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  3. Karl H. Jakobs
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Some of the data were presented in abstract form (Aktories et al., 1979a)

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Aktories, K., Schultz, G. & Jakobs, K.H. Regulation of adenylate cyclase activity in hamster adipocytes. Naunyn-Schmiedeberg's Arch. Pharmacol. 312, 167–173 (1980). https://doi.org/10.1007/BF00569726

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  • DOI: https://doi.org/10.1007/BF00569726

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