title: Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization.
abstract: Synaptic GTPase-activating protein (SynGAP) is a neuronal-specific Ras/Rap-GAP that increases the hydrolysis rate of GTP to GDP, converting Ras/Rap from the active into the inactive form. The Ras protein family modulates a wide range of cellular pathways including those involved in sensitization of sensory neurons. Since GAPs regulate Ras activity, SynGAP might be an important regulator of peripheral sensitization and pain. Therefore, we evaluated excitability, stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP), and nociception from wild-type (WT) mice and those with a heterozygous mutation of the SynGAP gene (SynGAP(+/-)). Our results demonstrate that SynGAP is expressed in primary afferent sensory neurons and that the capsaicin-stimulated CGRP release from spinal cord slices was two-fold higher from SynGAP(+/-) mice than that observed from WT mouse tissue, consistent with an increase in expression of the capsaicin receptor, transient receptor potential cation channel subfamily V member 1 (TRPV1), in SynGAP(+/-) dorsal root ganglia. However, there was no difference between the two genotypes in potassium-stimulated release of CGRP, the number of action potentials generated by a ramp of depolarizing current, or mechanical hypernociception elicited by intraplantar injection of capsaicin. In contrast, capsaicin-induced thermal hypernociception occurred at lower doses of capsaicin and had a longer duration in SynGAP(+/-) mice than WT mice. These results provide the first evidence that SynGAP is an important regulator of neuropeptide release from primary sensory neurons and can modulate capsaicin-induced hypernociception, demonstrating the importance of GAP regulation in signaling pathways that play a role in peripheral sensitization.
authors.affiliation: Department of Pharmacology and Toxicology and 2Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Djane Braz
authors.initials: DB
authors.lastname: Duarte
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Duan
authors.forename: Grant D
authors.initials: GD
authors.lastname: Nicol
authors.forename: Michael R
authors.initials: MR
authors.lastname: Vasko
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Hingtgen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology*; D002478:Cells, Cultured; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000139:chemically induced; D011188:Potassium / Q000502:physiology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D018689:Sensory System Agents / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000502:physiology; D020703:ras GTPase-Activating Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
chemical_list: D018689:Sensory System Agents; C484512:Syngap1 protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D020703:ras GTPase-Activating Proteins; D015740:Calcitonin Gene-Related Peptide; D011188:Potassium; D002211:Capsaicin