ACTH and adrenal aerobic glycolysis. I: Effects of O-nitrophenylsulphenyl and other ACTH analogues, vasoactive intestinal peptide and human parathyroid hormone(1–34) on lactic acid, steroid and cyclic AMP production by mouse adrenocortical cells

Author:

Hinson J.,Birmingham M. K.

Abstract

ABSTRACT The structural requirements in the ACTH molecule for evocation of the glycolytic response in suspensions of mouse adrenal cells were investigated by examining the effects of analogues containing modifications at positions 8,9 and 10 and of peptides containing homologies with the amino-terminal segment of ACTH. Introduction of a nitrophenylsulphenyl (NPS) group into the tryptophan moiety at position 9 of ACTH(1–24) greatly reduced both the potency and the capacity for maximal glycolytic response. It also virtually abolished cyclic AMP formation. In contrast, the capacity for a maximal steroidogenic response remained unimpaired in the NPS derivative, although steroidogenic potency was reduced to 0·4% of that of ACTH(1–24). Replacement of the tryptophan moiety with phenylalanine had intermediate inhibitory effects on glycolysis and steroid output; replacement with alanine virtually abolished both these responses. Replacement of arginine in position 8 with lysine in the Phe9 analogue caused a fifty-fold increase in glycolytic potency, but rendered it steroidogenically inactive. Cyclic AMP production was abolished in the Ala9 analogue and greatly impaired in the Phe9 and Lys8,Phe9 analogues. Replacement of the glycine moiety in position 10 with l-alanine, d-alanine, β-alanine or α-aminoisobutyric acid had little or no effect on steroidogenic or glycolytic capacity, although potency was reduced with all substitutions excepting l-alanine. Vasoactive intestinal peptide, which contains homologies with positions 3, 7, 15 and 16 of ACTH, proved completely inactive in dispersed mouse adrenal cells under our experimental conditions, in contrast to human parathyroid hormone(1–34) (hPTH (1–34)) which contains homologies with positions 3, 4, 5, 9 and 11 and was steroidogenic at the lowest concentration tested (0·1 nmol/l), eliciting an eleven-fold increase in steroid production, a response which might be physiologically relevant. It induced near maximal steroidogenesis at a concentration of 10 nmol/l, without affecting cyclic AMP production, and stimulated glycolysis at concentrations above 10 nmol/l, accompanied by a slight rise in cyclic AMP levels. The examples of dissociation between glycolysis and steroidogenesis suggest that different receptors may mediate the two responses. The examples of increased steroidogenesis unaccompanied by a rise in cyclic AMP accord with the concept that cyclic AMP is not an obligatory second messenger for the steroidogenic response. J. Endocr. (1987) 115, 61–69

Publisher

Bioscientifica

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism

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