Receptor channels activated by glutamate, an excitatory neurotransmitter in the mammalian brain, are involved in processes such as long-term potentiation and excitotoxicity. Studies of glutamate receptor channels expressed in cultured hippocampal pyramidal neurons reveal that these channels are subject to neuromodulatory regulation through the adenylate cyclase cascade. The whole-cell current response to glutamate and kainate [a non-NMDA (N-methyl-D-aspartate) receptor agonist] was enhanced by forskolin, an activator of adenylate cyclase. Single-channel analysis revealed that an adenosine 3',5'-monophosphate-dependent protein kinase (PKA) increases the opening frequency and the mean open time of the non-NMDA-type glutamate receptor channels. Analysis of synaptic events indicated that forskolin, acting through PKA, increased the amplitude and decay time of spontaneous excitatory postsynaptic currents.