REGULATION OF ALPHA(2)-ADRENERGIC RECEPTOR EXPRESSION AND SIGNALING IN PANCREATIC BETA-CELLS

Activation of alpha(2)-adrenergic receptors (alpha(2)-AR) in pancreatic beta-cells inhibits insulin secretion in response to various stimuli, and acute or long-term regulation of alpha(2)-AR receptor-mediated effects may influence the tissue response to glucose dishomeostasis. As an initial approach to this issue, we determined the effect of various metabolic and hormonal treatments on alpha(2)-AR expression and coupling in the pancreatic beta-cell lines HIT-T15 and RIN-5AH. Radioligand binding studies ([H-3]RX-821002) and RNA blot analysis indicate that both pancreatic beta-cell lines express the alpha(2A/D)-AR subtype [for HIT-T15 the maximum binding (B-max) = 113 +/- 28; for RIN-5AH B-max = 93 +/- 18 fmol/mg of cellular protein]. Treatment of HIT-TIS or RIN-5AH cells with glucocorticoids [dexamethasone, hydrocortisone, or prednisolone (1 mu M)] increased alpha(2)-AR mRNA level and receptor protein density three- to fivefold. The glucocorticoid-induced increase in receptor density in HIT-T15 cells was associated with 1) an increase in the amount of receptors coupled to G protein as determined by analysis of high-affinity 5'-guanylyl imidodiphosphate-sensitive binding of [H-3]UK-14304, a selective alpha(2)-AR agonist, and 2) a greater inhibition of forskolin-induced elevation of cellular adenosine 3',5'-cyclic monophosphate after receptor activation. Receptor density in HIT-T15 cells was not altered by different growth conditions, insulin (1 mu M), phorbol 12-myristate 13-acetate (1 mu M), or the sex steroids testosterone and progesterone (1 mu M). These data indicate that glucocorticoids upregulate alpha(2)-AR expression and signaling in pancreatic beta-cells. Such regulation may operate in a cell-specific manner, allowing discrete modulation of tissue responses to glucose dishomeostasis.