INDUCTION OF THE RAT PRODYNORPHIN GENE THROUGH GS-COUPLED RECEPTORS MAY INVOLVE PHOSPHORYLATION-DEPENDENT DEREPRESSION AND ACTIVATION

Prodynorphin transcription is activated via Gs-coupled receptors throu gh a cyclic AMP (cAMP)-dependent pathway. Four cAMP response elements (CREs) are present within the rat prodynorphin (RD) control region, an d all four CREs appear to function in RD regulation. Three CREs locate d upstream between -1860 and -1504 are critical for receptor-responsiv e activity, but their function is distance dependent unless they act t ogether with a fourth CRE found in exon 1. Regulation of RD also appea rs to involve multiple CRE-binding proteins. Both CRE-binding protein (CREB) and activator protein 1 (AP-1) can regulate RD, but their effec ts are in opposite directions; CREB represses and AP-1 activates RD. C REB-induced repression and AP-1 activation require distinct elements w ithin the control region, but their binding and functions overlap at C RE-3. While CREB repression is dependent on CRE-3, AP-1 activation (an d cAMP induction) of RD requires additional CREs (CRE-1, -2, and -4). CREB repression blocks AP-1 activation in unstimulated cells. However, phosphorylation relieves CREB-induced repression and enhances AP-1 ac tivation. Gs-coupled receptor activation of RD may require phosphoryla tion-dependent derepression and activation steps.