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Marcel Crest "Spécialisation fonctionnelle des canaux sodium"

Abstract :


Functional specialization of neuronal Na+ channels

A major challenge toward understanding the molecular determinants of the electroresponsiveness of neurons is to determine the properties of the Na+ currents, as they control subthreshold activity and action potential electrogenesis. Accordingly, our aim was to answer three main questions: First, which Na+ channel subunits are expressed in differentiated neurons, and what is their specific subcellular location? Second, what are the properties of the Na+ currents in a neuron cells in which these currents can be voltage-clamped adequately? Third, are the different components of the Na+ current attributable to channel heterogeneity and/or subcellular location? These questions were addressed in cerebellar granule cells and nociceptive sensory neurons.
We show that cerebellar granule cells display different spatial distribution of Nav1.2 and Nav1.6 isotypes in soma, AIS and dendrites. The specific contribution of these Na+ channels has been assessed using a combination of methods that allowed discrimination between functionally compartmentalized Na+ currents. We found that the Na+ current is dominated by the discrete localization of fast activating-fully inactivating Na+ channels that are prominently expressed at the AIS membrane and more sparsely represented in the soma plasma membrane. Cerebellar granule cells also exhibited a persistent Na+ current that makes up to ~ 3 % of the total Na+ current and that originates from non-somatic regions.
Nociceptive sensory neurons are unusual in expressing voltage-gated Na+ current carried by a large range of sodium channels some being sensitive and other resistant to block by tetrodotoxin (TTX). Expression of the channels mediating TTX resistant Na+ currents, Nav1.8 (SNS) and Nav1.9 (NaN) has been implicated in pain sensation. The SNS current activated quickly enough to carry 80% of the inward flux during the action potential. The NaN current activates slowly regulates the spike threshold and displays a persistent component. Various studies, however, have put the role of NaN into question, since some authors failed to detect this current in patch recordings. We clarified the voltage dependent properties of NaN and we proposed a model for the contribution of NaN in shaping the electrogenesis of nociceptive sensory neurons.

Selected publications

Lachamp P, Balland B, Tell F, Baude A, Strube C, Crest M, Kessler JP.
Early expression of AMPA receptors and lack of NMDA receptors in developing rat climbing fibre synapses.
J Physiol. 2005 May 1;564(Pt 3):751-63.
Bessone R, Martin-Eauclaire MF, Crest M, Mourre C.
Heterogeneous competition of Kv1 channel toxins with kaliotoxin for binding in rat brain: autoradiographic analysis.
Neurochem Int. 2004 Dec;45(7):1039-47.
Delmas P, Padilla F, Osorio N, Coste B, Raoux M, Crest M.
Polycystins, calcium signaling, and human diseases.
Biochem Biophys Res Commun. 2004 Oct 1;322(4):1374-83. Review.

Françoise Moos