title: Nerve injury induces a Gem-GTPase-dependent downregulation of P/Q-type Ca2+ channels contributing to neurite plasticity in dorsal root ganglion neurons.
abstract: Small RGK GTPases, Rad, Gem, Rem1, and Rem2, are potent inhibitors of high-voltage-activated (HVA) Ca(2+) channels expressed in heterologous expression systems. However, the role of this regulation has never been clearly demonstrated in the nervous system. Using transcriptional analysis, we show that peripheral nerve injury specifically upregulates Gem in mice dorsal root ganglia. Following nerve injury, protein expression was increased in ganglia and peripheral nerve, mostly under its phosphorylated form. This was confirmed in situ and in vitro in dorsal root ganglia sensory neurons. Knockdown of endogenous Gem, using specific small-interfering RNA (siRNA), increased the HVA Ca(2+) current only in the large-somatic-sized neurons. Combining pharmacological analysis of the HVA Ca(2+) currents together with Gem siRNA-transfection of larger sensory neurons, we demonstrate that only the P/Q-type Ca(2+) channels were enhanced. In vitro analysis of Gem affinity to various CaVβx-CaV2.x complexes and immunocytochemical studies of Gem and CaVβ expression in sensory neurons suggest that the specific inhibition of the P/Q channels relies on both the regionalized upregulation of Gem and the higher sensitivity of the endogenous CaV2.1-CaVβ4 pair in a subset of sensory neurons including the proprioceptors. Finally, pharmacological inhibition of P/Q-type Ca(2+) current reduces neurite branching of regenerating axotomized neurons. Taken together, the present results indicate that a Gem-dependent P/Q-type Ca(2+) current inhibition may contribute to general homeostatic mechanisms following a peripheral nerve injury.
authors.affiliation: Inserm U1051, Institut des Neurosciences, 80 rue Augustin Fliche, 34091, Montpellier, France, frederique.scamps@inserm.fr.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Scamps
authors.forename: Sina
authors.initials: S
authors.lastname: Sangari
authors.forename: Melissa
authors.initials: M
authors.lastname: Bowerman
authors.forename: Mathieu
authors.initials: M
authors.lastname: Rousset
authors.forename: Michel
authors.initials: M
authors.lastname: Bellis
authors.forename: Thierry
authors.initials: T
authors.lastname: Cens
authors.forename: Pierre
authors.initials: P
authors.lastname: Charnet
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009416:Nerve Regeneration; D016501:Neurites / Q000378:metabolism* / Q000502:physiology; D009473:Neuronal Plasticity; D059348:Peripheral Nerve Injuries / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020559:Monomeric GTP-Binding Proteins; C088119:Gem protein, mouse