Metabotropic glutamate receptors, unlike ionotropic receptors, exert their actions on ion channels via G-proteins coupled to second messenger systems. In the hippocampus stimulation of metabotropic receptors can lead to decreased potassium channel conductance, decreased accommodation of cell firing and inhibition of the slow calcium-dependent afterhyperpolarizing current (IAHP). Using the single-electrode voltage-clamp technique in hippocampal slice cultures of the rat, the role of protein kinases in mediating these metabotropic glutamate responses was investigated. In the presence of staurosporin, protein kinase C activation by phorbol esters and protein kinase A activation by 8-bromo-cyclic adenosine monophosphate were blocked. Under these conditions, the inhibition of IAHP by 1-amino-cyclopentyl-trans-dicarboxylate (ACPD), a metabotropic agonist, was unchanged, whilst the inward current elicited by ACPD was enhanced. These results demonstrate that, in the hippocampus, metabotropic glutamate responses persist during inhibition of protein kinase A and C activation. Furthermore, these responses are insensitive to pertussis toxin, confirming previous observations.