title: Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide.
abstract: The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is secreted by both neuronal and non-neuronal cells in the brain and spinal cord, in response to pathological conditions such as stroke, seizures, chronic inflammatory and neuropathic pain. PACAP has been shown to exert various neuromodulatory and neuroprotective effects. However, direct influence of PACAP on the function of intrinsically excitable ion channels that are critical to both hyperexcitation as well as cell death, remain largely unexplored. The major dendritic K(+) channel Kv4.2 is a critical regulator of neuronal excitability, back-propagating action potentials in the dendrites, and modulation of synaptic inputs. We identified, cloned and characterized the downstream signaling originating from the activation of three PACAP receptor (PAC1) isoforms that are expressed in rodent hippocampal neurons that also exhibit abundant expression of Kv4.2 protein. Activation of PAC1 by PACAP leads to phosphorylation of Kv4.2 and downregulation of channel currents, which can be attenuated by inhibition of either PKA or ERK1/2 activity. Mechanistically, this dynamic downregulation of Kv4.2 function is a consequence of reduction in the density of surface channels, without any influence on the voltage-dependence of channel activation. Interestingly, PKA-induced effects on Kv4.2 were mediated by ERK1/2 phosphorylation of the channel at two critical residues, but not by direct channel phosphorylation by PKA, suggesting a convergent phosphomodulatory signaling cascade. Altogether, our findings suggest a novel GPCR-channel signaling crosstalk between PACAP/PAC1 and Kv4.2 channel in a manner that could lead to neuronal hyperexcitability.
authors.affiliation: Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Raeesa P
authors.initials: RP
authors.lastname: Gupte
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Suraj
authors.initials: S
authors.lastname: Kadunganattil
authors.affiliation: Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Shepherd
authors.affiliation: Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Merrill
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: William
authors.initials: W
authors.lastname: Planer
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bruchas
authors.affiliation: Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Strack
authors.affiliation: Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA; Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, USA; Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mohapatrad@anest.wustl.edu.
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D051379:Mice; D016296:Mutagenesis / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000378:metabolism; D051672:Shal Potassium Channels / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C495504:Adcyap1r1 protein, mouse; D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051672:Shal Potassium Channels; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Extracellular-signal-regulated kinase (ERK); G protein-coupled receptor (GPCR); Ion channel modulation; Kv4.2; Pituitary adenylate cyclase-activating peptide (PACAP); Potassium channel; Protein kinase A (PKA)