Pituitary adenylate cyclase‐activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sI_AHPin CA1 pyramidal neurons by activating multiple signaling pathways

Abstract

The slow afterhyperpolarizing current (sIAHP) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sIAHP 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 sIAHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sIAHP, resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sIAHP by PACAP is mediated by PAC1 and VPAC1 receptors. Inhibition of PKA reduced the effect of PACAP on sIAHP, suggesting that PACAP exerts part of its inhibitory effect on sIAHP by increasing cAMP and activating PKA. The suppression of sIAHP 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 sIAHP. Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sIAHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sIAHP 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 sIAHP, 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.

Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide

“…Findings from our study indicate that these effects could possibly result from PACAP38-mediated reduction in Kv4.2 currents. Interestingly, it was also shown that PACAP reduces the slow afterhyperpolarizing currents (s I AHP ) in CA1 hippocampal pyramidal neurons, which resulted in increased AP firing frequency (Taylor et al, 2014). Therefore, in-depth future investigations are required to find out the relative contribution of PACAP-modulation of Kv4.2 vs s I AHP currents in the regulation of dendritic and overall neuronal excitability.…”

The Role of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signaling in the Hippocampal Dentate Gyrus

“…A few other studies have attempted to determine the role of PACAP in specific hippocampal subregions, especially the CA1. Hence, synaptic strength at the Schaeffer collateral synapse is sensitive to PACAP (Kondo et al, 1997;Roberto and Brunelli, 2000;Roberto et al, 2001;Ciranna and Cavallaro, 2003), which may be mediated by PACAP effects on AMPA currents (Costa et al, 2009;Toda and Huganir, 2015), NMDA currents (Macdonald et al, 2005), or other intrinsic channel mechanisms (Taylor et al, 2014). Behaviorally, PAC1 receptor knockout mice demonstrated decrements in several hippocampal-dependent tasks, such as foreground contextual fear conditioning (Sauvage et al, 2000), and background contextual fear conditioning (Otto et al, 2001).…”

Parallel signaling pathways of pituitary adenylate cyclase activating polypeptide (PACAP) regulate several intrinsic ion channels

“…PACAP, like many other neurotransmitters/neuropeptides, depresses a calcium‐dependent late slow outward potassium current in CA1 pyramidal cells . This slow outward current underlies the late slow component of the three‐component AHP that follows an AP in these neurons.…”

“…Part of this PACAP effect is mediated through PAC1 receptor activation, the remainder through activation of VPAC1 receptors. Activation of AC/cAMP/PKA and p38 MAPK signaling cascades mediates the PACAP modulation of the slow calcium‐dependent potassium current …”