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Pituitary adenylate cyclase‐activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sI AHP in CA1 pyramidal neurons by activating multiple signaling pathways
Author(s) -
Taylor Ruth D.T.,
Madsen Marita Grønning,
Krause Michael,
SampedroCastañeda Marisol,
Stocker Martin,
Pedarzani Paola
Publication year - 2014
Publication title -
hippocampus
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.767
H-Index - 155
eISSN - 1098-1063
pISSN - 1050-9631
DOI - 10.1002/hipo.22201
Subject(s) - adenylate kinase , chemistry , hippocampal formation , protein kinase a , signal transduction , camp dependent pathway , inhibitory postsynaptic potential , mapk/erk pathway , pituitary adenylate cyclase activating peptide , microbiology and biotechnology , neuroscience , receptor , kinase , neuropeptide , biology , vasoactive intestinal peptide , biochemistry
The slow afterhyperpolarizing current (sI AHP ) is a calcium‐dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sI AHP is a well‐known target of modulation by several neurotransmitters acting via the cyclic AMP (cAMP) and protein kinase A (PKA)‐dependent pathway. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its receptors are present in the hippocampal formation. In this study we have investigated the effect of PACAP on the sI AHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sI AHP , resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sI AHP by PACAP is mediated by PAC 1 and VPAC 1 receptors. Inhibition of PKA reduced the effect of PACAP on sI AHP , suggesting that PACAP exerts part of its inhibitory effect on sI AHP by increasing cAMP and activating PKA. The suppression of sI AHP by PACAP was also strongly hindered by the inhibition of p38 MAP kinase (p38 MAPK). Concomitant inhibition of PKA and p38 MAPK indicates that these two kinases act in a sequential manner in the same pathway leading to the suppression of sI AHP . Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sI AHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sI AHP through the activation of multiple signaling pathways, most prominently cAMP/PKA and p38 MAPK. Our findings disclose a novel modulatory action of p38 MAPK on intrinsic excitability and the sI AHP , underscoring the role of this current as a neuromodulatory hub regulated by multiple protein kinases in cortical neurons. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.