Mitogen activated protein kinases mediate endothelin regulation of tyrosine hydroxylase in the olfactory bulb

Abstract

Endothelins (ETs) function as neuromodulators in different brain areas including the olfactory bulbs (OB) which are connected with regions that regulate the cardiovascular activity and mood. We previously reported that ETs increase tyrosine hydroxylase (TH) activity through several pathways like PKA, PKC, and CaMKII. TH activity modifications are due to an augment in protein total levels, its phosphorylation forms at Ser 19, 31 and 40 as well as the level of TH mRNA. It is also known that ERK1/2 are late effect proteins which are known to phosphorylate TH and modulate its activity. In the present study we aimed to determine if ERK1/2 mediated ETs regulation of TH expression in the OB. ET‐1 and ET‐3 increased ERK1/2 expression by 39% and 42%, respectively, but no changes were observed in phosphorylated ERK1/2. In the presence of PD98059 (ERK1/2 inhibitor) the increase of TH mRNA induced by ETs was abolished. In addition, the effect of ETs in total protein levels was partially blocked by ERK inhibitor presence. However, the level of TH phosphorylation at Ser 40, were totally reduced. These findings indicate that ETs modulated TH mRNA and protein levels through ERK1/2. Since Ser 40 phosphorylation has the major impact on TH activation, we suggest that ERK1/2 might be increasing TH activity by this mechanism. (ANPCyT, CONICET, UBA)