Intracellular signaling mechanisms underlying the activity and internalization of the neuronal norepinephrine transporter by endothelin‐3 in the rat posterior hypothalamus

Abstract

Brain norepinephrine (NE) is involved in relevant physiological functions regulated by the hypothalamus. We previously reported that endothelins (ET) participate in the short term regulation of NE uptake in the anterior and posterior hypothalamus by changing the kinetic and internalization of the neuronal NE transporter (NET). In the present work we studied the mechanisms involved in the regulation of NET by ET‐3 in the rat posterior hypothalamic region (PHR). Experiments were performed in vitro and neuronal NE uptake and nisoxetine binding were used as indexes of activity and internalization of NET, respectively. Results showed that ET‐3 reduced neuronal NE uptake through the activation of a non conventional ET receptor involving PKC, PKA and PKG pathways. Furthermore ET‐3 enhanced NET internalization. However incubation with inhibitors of PKC (GF‐109203x), PKA (H‐89) or PKG (KT5823) inhibited ET‐3 response on NET internalization. Present findings suggest that the effect of ET‐3 on NET in the rat PHR is mediated by a non‐conventional ET receptor coupled to various intracellular pathways including PKC, PKA and PKG.(UBACyT B079, CONICET‐PIP 5929, ANPCyT PICT‐38333)