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

Raeesa P Gupte; Suraj Kadunganattil; Andrew J Shepherd; Ronald Merrill; William Planer; Michael R Bruchas; Stefan Strack; Durga P Mohapatra

doi:10.1016/j.neuropharm.2015.10.006

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

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

Raeesa P Gupte, Suraj Kadunganattil, Andrew J Shepherd, Ronald Merrill, William Planer, Michael R Bruchas, Stefan Strack and Durga P Mohapatra

Neuropharmacology, Vol.101, pp.291-308

02/2016

DOI: 10.1016/j.neuropharm.2015.10.006

PMCID: PMC4681664

PMID: 26456351

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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. [Display omitted] •PACAP activation of hippocampal PAC1 isoforms leads to PKA and ERK1/2 activation.•The major dendritic K+ channel Kv4.2 is dynamically downregulated by PAC1/PKA/ERK1/2 signaling.•Convergence of PKA and ERK1/2, and phosphorylation of Kv4.2 by the later reduces channel density.•PACAP modulation of Kv4.2 is not influenced by voltage-dependence of channel activation.

Ion channel modulation

Pituitary adenylate cyclase-activating peptide (PACAP)

Extracellular-signal-regulated kinase (ERK)

G protein-coupled receptor (GPCR)

Kv4.2

Protein kinase A (PKA)

Potassium channel

Details

Title: Subtitle: Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide
Creators: Raeesa P Gupte - Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA
Suraj Kadunganattil - Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Andrew J Shepherd - Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA
Ronald Merrill - Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA
William Planer - Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Michael R Bruchas - Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA
Stefan Strack - Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA
Durga P Mohapatra - Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Neuropharmacology, Vol.101, pp.291-308
DOI: 10.1016/j.neuropharm.2015.10.006
PMID: 26456351
PMCID: PMC4681664
NLM abbreviation: Neuropharmacology
ISSN: 0028-3908
eISSN: 1873-7064
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100000002, name: NIH, award: NINDS-NS069898, NINDS-NS056244, NIDA-DA034929; DOI: 10.13039/100008893, name: University of Iowa; name: Washington University School of Medicine; name: Washington University Pain Center
Language: English
Date published: 02/2016
Academic Unit: Pathology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984040442902771

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