Phosphorylation of transcription factor cyclic-AMP response element binding protein mediates c-fos induction elicited by sustained hypertension in rat nucleus tractus solitarii

We investigated the role of cyclic-AMP response element binding protein sig naling in the induction of the immediate-early gene c-fos by baroreceptor a ctivation in neurons of the nucleus tractus solitarii of anesthetized rats. Activation of the arterial baroreceptors with sustained hypertension signi ficantly increased the number of neurons in the caudal nucleus tractus soli tarii that were immunoreactive to an antiserum that detects Ser(133)-phosph orylated cyclic-AMP response element binding protein. This implied increase in phosphorylation of cyclic-AMP response element binding protein was subs equently followed by an elevation in the expression of Fos protein in neuro ns of the nucleus tractus solitarii. Microinjection bilaterally into the nu cleus tractus solitarii of a phosphorothioated antisense oligonucleotide di rected against the initiation site of cyclic-AMP response element binding p rotein messenger RNA discernibly reduced the manifested immunoreactivity of phosphorylated cyclic-AMP response element binding protein in response to baroreceptor activation. This was accompanied by a decline in the transcrip tion of c-fos messenger RNA and the expression of Fos protein, along with a n appreciable potentiation of the baroreceptor reflex response. Control inj ections of the sense oligonucleotide or artificial cerebrospinal fluid were ineffective. These findings suggest that phosphorylation of cyclic-AMP response element binding protein is crucial to Fos expression in the nucleus tractus solitar ii elicited by sustained hypertension. As such, phosphorylation of cyclic-A MP response element binding protein may be an important early nuclear event that mediates the long-term inhibitory modulation of the baroreceptor refl ex response by Fos protein at the nucleus tractus solitarii. (C) 1998 IBRO. Published by Elsevier Science Ltd.