Protein Kinase A Mediates the Modulation of the Slow Ca-Dependent K Current, IsAHP, by the Neuropeptides CRF, VIP, and CGRP in Hippocampal Pyramidal Neurons

Haug, Trude and Johan F. Storm. Protein kinase A mediates the modulation of the slow Ca-dependent K current, IsAHP, by the neuropeptides CRF, VIP, and CGRP in hippocampal pyramidal neurons. J. Neurophysiol. 83: 2071–2079, 2000. We have studied modulation of the slow Ca-activated K current (IsAHP) in CA1 hippocampal pyramidal neurons by three peptide transmitters: corticotropin releasing factor (CRF, also called corticotropin releasing hormone, CRH), 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 mM) and tetraethylammonium (TEA, 5 mM), IsAHP was measured after a brief depolarizing voltage step eliciting inward Ca current. Each of the peptides CRF (100–250 nM), VIP (400 nM), and CGRP (1 mM) significantly reduced the amplitude of IsAHP. Thus the IsAHP 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 mM CGRP. We found no consistent concomitant changes in the Ca current or in the time course of IsAHP for any of the three peptides, suggesting that the suppression of IsAHP was not secondary to a general suppression of Ca channel activity. Because each of these peptides is known to activate the cyclic AMP (cAMP) cascade in various cell types, and IsAHP is known to be suppressed by cAMP via the cAMP-dependent protein kinase (PKA), we tested whether the effects on IsAHP by CRF, VIP, and CGRP are mediated by PKA. Intracellular application of the PKA-inhibitor Rp-cAMPS significantly reduced the suppression of IsAHP by CRF, VIP, and CGRP. Thus with 1 mM Rp-cAMPS in the recording pipette, the average suppression of IsAHP 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 mM CGRP. We conclude that CRF, VIP, and CGRP suppress the slow Ca-activated K current, IsAHP, 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 IsAHP.