Dopamine D1 Receptor Activation Mediates GAD 67 Inhibition by Intermittent Hypoxia

Intermittent hypoxia (IH) has been shown to alter neurotransmitter synthesis. GABA, a major inhibitory neurotransmitter in the central nervous system, is implicated in cardio‐respiratory control and its synthesis is primarily catalyzed by glutamic acid decarboxylase (GAD). In the present study, we examined the effect of IH on GABA synthesis and determined the underlying mechanisms using a pheochromocytoma 12 (PC12) cell line. IH decreased GAD67 activity and GABA levels. IH‐evoked decrease in GAD67 activity was due to increased cAMP ‐ protein kinase A (PKA) ‐ dependent phosphorylation of GAD67, but not due to changes in either GAD67 mRNA or protein expression. PKA but not PKC inhibitor restored GAD67 activity and GABA levels in IH treated cells. PC12 cells express dopamine D1 receptor (D1R), a G‐protein coupled receptor whose activation increased adenylyl cyclase (AC) activity. Treatment with either D1R antagonist or silencing D1R expression with siRNA reversed GAD67 inhibition by IH. These results provide evidence for the role of D1R signaling in IH mediated inhibition of GAD67 and the ensuing down regulation of GABA synthesis (Supported by HL‐89616 and HL‐90554).