TY - JOUR
T1 - Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide
AU - Gupte, Raeesa P.
AU - Kadunganattil, Suraj
AU - Shepherd, Andrew J.
AU - Merrill, Ronald
AU - Planer, William
AU - Bruchas, Michael R.
AU - Strack, Stefan
AU - Mohapatra, Durga P.
N1 - Funding Information:
This work was supported by NIH grants NINDS-NS069898 (to DPM), and NINDS-NS056244 (to SS) and NIDA-DA034929 (to MRB), as well as by start-up funds from the Office of the Vice President of Research, University of Iowa , and Washington University School of Medicine , Department of Anesthesiology and Washington University Pain Center (to DPM). The authors declare no competing financial interests. The authors wish to thank Dr. Robert W. Gereau IV (Washington University School of Medicine) and Drs. Christopher J. Benson, Yuriy M. Usachev and Amy Lee (University of Iowa Carver College of Medicine) for their critical suggestions on this work.
Publisher Copyright:
© 2015 Elsevier Ltd. All Rights Reserved.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
KW - Extracellular-signal-regulated kinase (ERK)
KW - G protein-coupled receptor (GPCR)
KW - Ion channel modulation
KW - Kv4.2
KW - Pituitary adenylate cyclase-activating peptide (PACAP)
KW - Potassium channel
KW - Protein kinase A (PKA)
UR - http://www.scopus.com/inward/record.url?scp=84944266180&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2015.10.006
DO - 10.1016/j.neuropharm.2015.10.006
M3 - Article
C2 - 26456351
AN - SCOPUS:84944266180
VL - 101
SP - 291
EP - 308
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -