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Overview

Author: Kuplast, Kristy ; Snutch, Terrance P. ; Pajouhesh, Hassan ; Eduljee, Cyrus ; Mezeyova, Janette ; Tringham, Elizabeth ; Smith, Paula ; Weerapura, Manjula ; Braine, Emma ; Jones, Nigel C. ; Cain, Stuart M. ; Morrison, Jerrie-Lynn ; Powell, Kim L. ; Rind, Gil ; Parmar, Manjeet ; O’Brien, Terence J. ; Fee-Maki, Molly ; Parker, David ; Jiang, Xinpo

Two high-affinity T-type calcium channel blockers attenuate neural activity in the thalamus and suppress seizures in a genetic model of absence epilepsy.

05 Jul 2011·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome

Q1 · CROSS-FIELD

Article

Author: Ferrer, Juan F. Sanguesa ; Matricon, Julien ; Pizzoccaro, Anne ; Nargeot, Joël ; Bourinet, Emmanuel ; Snutch, Terrance P. ; Ardid, Denis ; Barrère, Christian ; Muller, Emilie ; Eschalier, Alain ; Gelot, Agathe ; Marger, Fabrice ; Alloui, Abdelkrim

The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the CaV3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyrate-mediated rodent model of IBS. Both the selective genetic inhibition of CaV3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of CaV3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant CaV3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest CaV3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.

01 Jan 2011·Molecular PainQ3 · MEDICINE

Identification of Sodium Channel Isoforms That Mediate Action Potential Firing in Lamina I/II Spinal Cord Neurons

Q3 · MEDICINE

ArticleOA

Author: Salter, Michael W ; Smith, Paula L ; Hildebrand, Michael E ; Snutch, Terrance P ; Mezeyova, Janette ; Tringham, Elizabeth

Background: Voltage-gated sodium channels play key roles in acute and chronic pain processing. The molecular, biophysical, and pharmacological properties of sodium channel currents have been extensively studied for peripheral nociceptors while the properties of sodium channel currents in dorsal horn spinal cord neurons remain incompletely understood. Thus far, investigations into the roles of sodium channel function in nociceptive signaling have primarily focused on recombinant channels or peripheral nociceptors. Here, we utilize recordings from lamina I/II neurons withdrawn from the surface of spinal cord slices to systematically determine the functional properties of sodium channels expressed within the superficial dorsal horn. Results: Sodium channel currents within lamina I/II neurons exhibited relatively hyperpolarized voltage-dependent properties and fast kinetics of both inactivation and recovery from inactivation, enabling small changes in neuronal membrane potentials to have large effects on intrinsic excitability. By combining biophysical and pharmacological channel properties with quantitative real-time PCR results, we demonstrate that functional sodium channel currents within lamina I/II neurons are predominantly composed of the NaV1.2 and NaV1.3 isoforms. Conclusions: Overall, lamina I/II neurons express a unique combination of functional sodium channels that are highly divergent from the sodium channel isoforms found within peripheral nociceptors, creating potentially complementary or distinct ion channel targets for future pain therapeutics.

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