A detailed study on the effects of protein kinase C activation on alpha-2 adrenoceptor-coupled modulation of norepinephrine release in hippocampus.

The question was studied whether there is a direct link between protein kinase C and presynaptic alpha-2 adrenoceptors regulating depolarization-induced norepinephrine (NE) release. Effects of the protein kinase C activator 4 beta-phorbol 12,13-dibutyrate (4 beta-PDB) on electrically evoked [3H]NE release were investigated in rabbit and rat hippocampus. Release evoked with 4 pulses/100 Hz (POP stimulation; i.e. under conditions virtually free of autoinhibition), was increased by 4 beta-PDB in a comparable manner in both species. Conversely, the alpha-2 adrenoceptor agonist clonidine diminished POP-induced [3H]NE release in a concentration-dependent manner. The net effects of clonidine were of a similar magnitude up to near maximal concentrations, irrespective of whether or not the 4 beta-PDB was present. Correspondingly, the net effect of 4 beta-PDB remained unchanged under these conditions. An impairment of the net effect of 4 beta-PDB was only seen at higher concentrations of clonidine. Concurrent addition of the alpha-2 adrenoceptor antagonist yohimbine and 4 beta-PDB enhanced release elicited with 36 pulses/3 Hz (i.e., in presence of autoinhibition), in a manner which was at least additive. Taken together, the above data exclude a direct link between presynaptic alpha-2 adrenoceptors and protein kinase C and restrict a functional interaction to very distinctive conditions.