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 ([3H]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 (Bmax) = 113 +/- 28; for RIN-5AH Bmax = 93 +/- 18 fmol/mg of cellular protein]. Treatment of HIT-T15 or RIN-5AH cells with glucocorticoids [dexamethasone, hydrocortisone, or prednisolone (1 microM)] 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 [3H]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 microM), phorbol 12-myristate 13-acetate (1 microM), or the sex steroids testosterone and progesterone (1 microM). 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.
Hamamdzic
D
D
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston 29425, USA.
Duzic
E
E
Sherlock
J D
JD
Lanier
S M
SM
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003907:Dexamethasone / Q000494:pharmacology; D007515:Islets of Langerhans / Q000502:physiology*; D008647:Mesocricetus; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
D011942:Receptors, Adrenergic, alpha; D003907:Dexamethasone