VIP enhances synaptic transmission to hippocampal CA1 pyramidal cells through activation of both VPAC1 and VPAC2 receptors

Abstract We previously described that vasoactive intestinal peptide (VIP) increases synaptic transmission to hippocampal CA1 pyramidal cells at concentrations known to activate VIP-selective receptors (VPAC 1 and VPAC 2 ) but not the PACAP-selective PAC 1 receptor. We now investigated the involvement of VPAC 1 and VPAC 2 receptors in the effects elicited by VIP as well as the transduction pathways activated by VIP to cause enhancement of synaptic transmission. Blockade of either VPAC 1 or VPAC 2 receptors with PG 97–269 (100 nM) or PG 99–465 (100 nM) inhibited VIP-induced enhancement of synaptic transmission. Selective activation of VPAC 1 receptors with [K 15 , R 16 , L 27 ] VIP(1–7)/GRF(8–27) (10 nM) or of VPAC 2 receptors with RO 25–1553 (10 nM) increased synaptic transmission to CA1 pyramidal cells, and this increase was larger when both agonists were applied together. Inhibition of either PKA with H-89 (1 μM) or PKC with GF109203X (1 μM) attenuated the effect of VIP (1 nM). GF109203X (1 μM) abolished the effect of the VPAC 1 agonist [K 15 , R 16 , L 27 ] VIP(1–7)/GRF(8–27) (10 nM) on hippocampal synaptic transmission but that effect was not changed by H-89 (1 μM). The effect of RO 25–1553 (100 nM) obtained in the presence of both the PAC 1 and VPAC 1 antagonists, M65 (30 nM) and PG 97–269 (100 nM), was strongly inhibited by H-89 (1 μM) but not GF109203X (1 μM). It is concluded that VIP enhances synaptic transmission to CA1 pyramidal cell dendrites through VPAC 1 and VPAC 2 receptor activation. VPAC 1 -mediated actions are dependent on PKC activity, and VPAC 2 -mediated actions are responsible for the PKA-dependent actions of VIP on CA1 hippocampal transmission.