CK1 regulates NMDA receptor activity through protein phosphatase‐1 in hypothalamic presympathetic neurons in hypertension

Abstract

Increased NMDA receptor (NMDAR) activity in hypothalamic paraventricular nucleus (PVN) contributes to high sympathetic outflow in hypertension. However, the mechanisms underlying augmented NMDAR activity remain unclear. Here, we determined whether casein kinase 1 (CK1) and protein phosphatase‐1 (PP1) are involved in the regulation of NMDAR activity in hypertension. We recorded evoked NMDAR‐ and AMPA receptor (AMPAR)‐ excitatory postsynaptic currents (EPSCs) and NMDAR currents elicited by puff NMDA in spinally projecting PVN neurons in spontaneously hypertensive rats (SHR) and Sprauge‐Dawley (SD) rats. The basal NMDAR‐EPSCs and puff NMDAR currents were significantly higher in SHR than in SD rats. Pretreatment with the CK1ε selective inhibitor PF4800567 or the PP1 inhibitor tautomycetin alone significantly increased the ratio of NMDAR‐EPSCs to AMPAR‐EPSCs and puff NMDAR currents of PVN neurons in SD rats. PF4800567 did not further increase the ratio of NMDAR‐EPSCs to AMPAR‐EPSCs and puff NMDAR currents caused by tautomycetin in SD rats. However, treatment with PF4800567 or tautomycetin had no effect on the ratio of NMDAR‐EPSCs to AMPAR‐EPSCs and puff NMDAR currents in SHR. These data suggest that CK1 regulates NMDAR activity through PP1 in hypothalamic presympathetic neurons and that diminished CK1 activity may contribute to augmented NMDAR function and hyperactivity of PVN neurons in hypertension.