PMID- 28363781
OWN - NLM
STAT- MEDLINE
DCOM- 20180208
LR  - 20180907
IS  - 1873-7544 (Electronic)
IS  - 0306-4522 (Linking)
VI  - 351
DP  - 2017 May 20
TI  - Hyperpolarization-activated current I(h) in mouse trigeminal sensory neurons in a 
      transgenic mouse model of familial hemiplegic migraine type-1.
PG  - 47-64
LID - S0306-4522(17)30199-9 [pii]
LID - 10.1016/j.neuroscience.2017.03.033 [doi]
AB  - Transgenic knock-in (KI) mice that express Ca(V)2.1 channels containing an R192Q 
      gain-of-function mutation in the alpha(1A) subunit known to cause familial hemiplegic 
      migraine type-1 in patients, exhibit key disease characteristics and provide a 
      useful tool to investigate pathophysiological mechanisms of pain transduction. 
      Previously, KI trigeminal sensory neurons were shown to exhibit constitutive 
      hyperexcitability due to up-regulation of ATP-gated P2X3 receptors that trigger 
      spike activity at a more negative threshold. This implies that intrinsic neuronal 
      conductances may shape action potential generation in response to ATP, which 
      could act as a mediator of migraine headache. Here we investigated whether the 
      hyperpolarization-activated conductance I(h), mediated by hyperpolarization 
      activated cyclic nucleotide-gated channels (HCN), contributes to sub-threshold 
      behavior and firing in wild-type (WT) and KI trigeminal ganglia (TG) neurons. 
      Whereas most WT and KI trigeminal neurons expressed I(h) current, blocked by the 
      specific inhibitor ZD7288, it was smaller in KI neurons despite similar 
      activation and deactivation kinetics. HCN1 and HCN2 were the most abundantly 
      expressed subunits in TG, both in situ and in culture. In KI TG neurons, HCN2 
      subunits were predominantly present in the cytoplasm, not at the plasma membrane, 
      likely accounting for the smaller I(h) of such cells. ZD7288 hyperpolarized the 
      membrane potential, thereby raising the firing threshold, and prolonging the 
      spike trajectory to generate fewer spikes due to P2X3 receptor activation. The 
      low amplitude of I(h) in KI TG neurons suggests that down-regulation of I(h) 
      current in sub-threshold behavior acts as a compensatory mechanism to limit 
      sensory hyperexcitability, manifested under certain stressful stimuli.
CI  - Copyright (c) 2017 IBRO. Published by Elsevier Ltd. All rights reserved.
FAU - Eroli, Francesca
AU  - Eroli F
AD  - Neuroscience Department, International School for Advanced Studies (SISSA), 
      Trieste, Italy. Electronic address: feroli@sissa.it.
FAU - Vilotti, Sandra
AU  - Vilotti S
AD  - Neuroscience Department, International School for Advanced Studies (SISSA), 
      Trieste, Italy. Electronic address: vilotti@sissa.it.
FAU - van den Maagdenberg, Arn M J M
AU  - van den Maagdenberg AMJM
AD  - Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands; 
      Department of Human Genetics, University Medical Centre, Leiden, Netherlands. 
      Electronic address: A.M.J.M.van_den_Maagdenberg@lumc.nl.
FAU - Nistri, Andrea
AU  - Nistri A
AD  - Neuroscience Department, International School for Advanced Studies (SISSA), 
      Trieste, Italy. Electronic address: nistri@sissa.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170329
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Purinergic P2X3)
RN  - 133059-99-1 (ICI D2788)
RN  - Hemiplegic migraine, familial type 1
SB  - IM
MH  - Action Potentials/drug effects
MH  - Animals
MH  - Cerebellar Ataxia/chemically induced/genetics/metabolism/*physiopathology
MH  - Disease Models, Animal
MH  - Gene Knock-In Techniques/methods
MH  - Membrane Potentials/drug effects
MH  - Mice, Transgenic
MH  - Migraine Disorders/chemically induced/genetics/metabolism/*physiopathology
MH  - Pyrimidines/pharmacology
MH  - Receptors, Purinergic P2X3/genetics/metabolism
MH  - Sensory Receptor Cells/*drug effects/metabolism
MH  - Trigeminal Ganglion/*drug effects/metabolism
OTO - NOTNLM
OT  - CGRP
OT  - HCN
OT  - P2X3
OT  - ZD7288
OT  - excitability
OT  - trigeminal ganglion
EDAT- 2017/04/02 06:00
MHDA- 2018/02/09 06:00
CRDT- 2017/04/02 06:00
PHST- 2016/11/24 00:00 [received]
PHST- 2017/03/15 00:00 [revised]
PHST- 2017/03/20 00:00 [accepted]
PHST- 2017/04/02 06:00 [pubmed]
PHST- 2018/02/09 06:00 [medline]
PHST- 2017/04/02 06:00 [entrez]
AID - S0306-4522(17)30199-9 [pii]
AID - 10.1016/j.neuroscience.2017.03.033 [doi]
PST - ppublish
SO  - Neuroscience. 2017 May 20;351:47-64. doi: 10.1016/j.neuroscience.2017.03.033. 
      Epub 2017 Mar 29.