Dual pancreatic adrenergic and dopaminergic signaling as a therapeutic target of bromocriptine.

Bromocriptine is approved as a diabetes therapy, yet its therapeutic mechanisms remain unclear. Though bromocriptine's actions have been mainly attributed to the stimulation of brain dopamine D receptors (D2R), bromocriptine also targets the pancreas. Here, we employ bromocriptine as a tool to elucidate the roles of catecholamine signaling in regulating pancreatic hormone secretion. In β-cells, bromocriptine acts on D2R and α-adrenergic receptor (α-AR) to reduce glucose-stimulated insulin secretion (GSIS). Moreover, in α-cells, bromocriptine acts via D2R to reduce glucagon secretion. α-AR activation by bromocriptine recruits an ensemble of G proteins with no β-arrestin2 recruitment. In contrast, D2R recruits G proteins and β-arrestin2 upon bromocriptine stimulation, demonstrating receptor-specific signaling. Docking studies reveal distinct bromocriptine binding to α-AR versus D2R, providing a structural basis for bromocriptine's dual actions on β-cell α-AR and D2R. Together, joint dopaminergic and adrenergic receptor actions on α-cell and β-cell hormone release provide a new therapeutic mechanism to improve dysglycemia.