Protein kinase A mediates the modulation of the slow Ca2+-dependent K+ current, IsAHP, by the neuropeptides CRF, VIP, and CGRP in hippocampal pyramidal neurons

We have studied modulation of the slow Ca2+-activated K+ current (I-sAHP) in CA1 hippocampal pyramidal neurons by three peptide transmitters: corticotropin releasing factor (CRF, also called corticotropin releasing hormone, CRI I), vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP). These peptides are known to be expressed in interneurons. Using whole cell voltage clamp in hippocampal slices from young rats, in the presence of tetrodotoxin (TTX, 0.5 mu M) and tetraethylammonium (TEA, 5 mM), I-sAHP was measured after a brief depolarizing voltage step eliciting inward Ca2+ current. Each of the peptides CRF (100-250 nM), VIP (400 nM), acid CGRP (1 mu M) significantly reduced che amplitude of I-sAHP. Thus the I-sAHP amplitude was reduced to 22% by 100 nM CRF, to 17% by 250 nM CRF, to 22% by 400 nM VIP, and to 40% by 1 mu M CGRP. We found no consistent concomitant changes in the Ca2+ current or in the time course of I-sAHP for any of the three peptides, suggesting that the suppression of I-sAHP was not secondary to a general suppression of Ca2+ channel activity. Because each of these peptides is known to activate the cyclic AMP (cAMP) cascade in various cell types, and I-sAHP is known to be suppressed by cAMP via the cAMP-dependent protein kinase (PKA), we tested whether the effects on I-sAHP by CRF, VIP, and CGRP are mediated by PKA. Intracellular application of the PKA-inhibitor Rp-cAMPS significantly reduced the suppression of I-sAHP by CRF, VIP, and CGRP. Thus with 1 mM Rp-cAMPS in the recording pipette, the average suppression of I-sAHP was reduced from 78 to 26% for 100 nM CRF, from 83 to 32% for 250 nM CRF, from 78 to 30% for 400 nM VIP, and from 60 to 7% for 1 mu M CGRP. We conclude that: CRF, VIP, and CGRP suppress the slow Ca2+-activated K+ current, I-sAHP, in CA1 hippocampal pyramidal neurons by activating the cAMP-dependent protein kinase, PKA. Together with the monoamine transmitters norepinephrine, serotonin, histamine, and dopamine, these peptide transmitters all converge on the cAMP cascade modulating I-sAHP.