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1.
PLoS One ; 6(9): e25508, 2011.
Article in English | MEDLINE | ID: mdl-21980481

ABSTRACT

M-channels are voltage-gated potassium channels composed of Kv7.2-7.5 subunits that serve as important regulators of neuronal excitability. Calmodulin binding is required for Kv7 channel function and mutations in Kv7.2 that disrupt calmodulin binding cause Benign Familial Neonatal Convulsions (BFNC), a dominantly inherited human epilepsy. On the basis that Kv7.2 mutants deficient in calmodulin binding are not functional, calmodulin has been defined as an auxiliary subunit of Kv7 channels. However, we have identified a presumably phosphomimetic mutation S511D that permits calmodulin-independent function. Thus, our data reveal that constitutive tethering of calmodulin is not required for Kv7 channel function.


Subject(s)
Calmodulin/metabolism , KCNQ2 Potassium Channel/metabolism , KCNQ3 Potassium Channel/metabolism , Amino Acid Sequence , Animals , Cell Membrane/metabolism , Gene Expression Regulation , HEK293 Cells , Humans , KCNQ2 Potassium Channel/chemistry , KCNQ2 Potassium Channel/genetics , KCNQ3 Potassium Channel/chemistry , KCNQ3 Potassium Channel/genetics , Molecular Sequence Data , Mutation , Protein Structure, Secondary , Protein Transport
2.
Front Behav Neurosci ; 3: 60, 2010.
Article in English | MEDLINE | ID: mdl-20204153

ABSTRACT

Panic disorder is a highly prevalent neuropsychiatric disorder that shows co-occurrence with substance abuse. Here, we demonstrate that TrkC, the high-affinity receptor for neurotrophin-3, is a key molecule involved in panic disorder and opiate dependence, using a transgenic mouse model (TgNTRK3). Constitutive TrkC overexpression in TgNTRK3 mice dramatically alters spontaneous firing rates of locus coeruleus (LC) neurons and the response of the noradrenergic system to chronic opiate exposure, possibly related to the altered regulation of neurotrophic peptides observed. Notably, TgNTRK3 LC neurons showed an increased firing rate in saline-treated conditions and profound abnormalities in their response to met(5)-enkephalin. Behaviorally, chronic morphine administration induced a significantly increased withdrawal syndrome in TgNTRK3 mice. In conclusion, we show here that the NT-3/TrkC system is an important regulator of neuronal firing in LC and could contribute to the adaptations of the noradrenergic system in response to chronic opiate exposure. Moreover, our results indicate that TrkC is involved in the molecular and cellular changes in noradrenergic neurons underlying both panic attacks and opiate dependence and support a functional endogenous opioid deficit in panic disorder patients.

3.
Br J Pharmacol ; 156(4): 649-61, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19226256

ABSTRACT

BACKGROUND AND PURPOSE: Locus coeruleus (LC) neurons respond to sensory stimuli with a glutamate-triggered burst of spikes followed by an inhibition. The aim of our work was to characterize the inhibitory effect of glutamate in the LC. EXPERIMENTAL APPROACH: Single-unit extracellular and patch-clamp recordings were performed to examine glutamate responses in rat brain slices containing the LC. KEY RESULTS: Glutamate caused an initial activation followed by a late post-activation inhibition (PAI). Both effects were blocked by an AMPA/kainate receptor antagonist but not by NMDA or metabotropic glutamate receptor antagonists. All glutamate receptor agonists were able to activate neurons, but only AMPA and quisqualate caused inhibition. In neurons clamped at -60 mV, glutamate and AMPA induced inward, followed by outward, currents, with the latter reversing polarity at -110 mV. Glutamate-induced PAI was not modified by alpha(2)-adrenoceptor, micro opioid, A(1) adenosine and GABA(A/B) receptor antagonists or Ca(2+)-dependent release blockade, but it was reduced by raising the extracellular K(+) concentration. Glutamate-induced PAI was not affected by several potassium channel, Na(+)/K(+) pump, PKC and neuronal NO synthase inhibitors or lowering the extracellular Ca(2+) concentration. The Na(+)-activated K channel opener bithionol concentration-dependently potentiated glutamate-induced PAI, whereas partial (80%) Na(+) replacement reduced glutamate- and AMPA-induced PAI. Finally, reverse transcription polymerase chain reaction assays showed the presence of mRNA for the Ca(2+)-impermeable GluR2 subunit in the LC. CONCLUSIONS AND IMPLICATIONS: Glutamate induces a late PAI in the LC, which may be mediated by a novel postsynaptic Na(+)-dependent K(+) current triggered by AMPA/kainate receptors.


Subject(s)
Glutamic Acid/pharmacology , Locus Coeruleus/drug effects , Neurons/drug effects , Potassium Channels/physiology , Receptors, AMPA/physiology , Receptors, Kainic Acid/physiology , Sodium/metabolism , Synaptic Potentials/drug effects , Animals , Dose-Response Relationship, Drug , Electrodes , Excitatory Amino Acid Agonists/pharmacology , Locus Coeruleus/cytology , Locus Coeruleus/metabolism , Male , Neurons/metabolism , Patch-Clamp Techniques , Potassium Channels/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, AMPA/antagonists & inhibitors , Receptors, Glutamate/metabolism , Receptors, Kainic Acid/antagonists & inhibitors , Reverse Transcriptase Polymerase Chain Reaction
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