title: Activation of neurokinin 3 receptor increases Na(v)1.9 current in enteric neurons.
abstract: The intrinsic primary afferent neurons (IPANs) of the guinea pig enteric nervous system express Na(v)1.9 sodium channels that produce a persistent TTX-resistant current having a low activation threshold and slow gating kinetics. These neurons receive slow EPSPs induced mainly by the activation of neurokinin 3 receptors (NK3r). Here, we demonstrate that senktide, a specific NK3r agonist, potentiates the Na(v)1.9 current (I(Nav1.9)) in IPANs. Using whole-cell patch-clamp recordings from IPANs in duodenum longitudinal muscle/myenteric plexus preparations, we show that short (1-5 s) and long (up to 1 min) applications of senktide, increase the I(Nav1.9) peak current up to 13-fold. The effect, blocked by a NK3r antagonist SB235375 is transient, lasting approximately 2 min and is due to a negative shift of the activation voltage by approximately 20 mV and of fast inactivation by approximately 10 mV. As a consequence, the window current resulting from the product of the activation and fast inactivation curves is shifted and enlarged. The transient effect of senktide is likely to be due to the fast desensitization of NK3r. Protein kinase C (PKC) activation with phorbol or oleoyl acetylglycerol also increases I(Nav1.9), although persistently, by inducing similar voltage-dependent changes. Current-clamp experiments showed that I(Nav1.9) modulation by senktide lowers action potential threshold and increases excitability. The increase in I(Nav1.9) by NK3r activation is also likely to amplify slow EPSPs generated in the IPANs. These changes in excitability potentially have a profound effect on the entire enteric synaptic circuit and ultimately on gut motility and secretion.
authors.affiliation: UMR, CNRS/Université de la Méditerranée/Université Paul Cézanne, Marseille, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Copel
authors.forename: Nancy
authors.initials: N
authors.lastname: Osorio
authors.forename: Marcel
authors.initials: M
authors.lastname: Crest
authors.forename: Maurice
authors.initials: M
authors.lastname: Gola
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
authors.forename: Nadine
authors.initials: N
authors.lastname: Clerc
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D004075:Diglycerides / Q000494:pharmacology; D004386:Duodenum / Q000294:innervation*; D017615:Enteric Nervous System / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D005769:Gastrointestinal Motility; D006168:Guinea Pigs; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007700:Kinetics; D009130:Muscle, Smooth / Q000294:innervation*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D018042:Receptors, Neurokinin-3 / Q000187:drug effects / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000085:Acetates; D004075:Diglycerides; D020536:Enzyme Activators; C444647:N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide; D010446:Peptide Fragments; D011804:Quinolines; D018042:Receptors, Neurokinin-3; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C054724:senktide; D013373:Substance P; D015240:Phorbol 12,13-Dibutyrate; D013779:Tetrodotoxin; C038237:1-oleoyl-2-acetylglycerol; D012964:Sodium; D011493:Protein Kinase C