Specialized functions of Nav1.5 and Nav1.9 channels in electrogenesis of myenteric neurons in intact mouse ganglia.
Voltage-gated sodium (Nav) channels play a central role in gastrointestinal physiology because they transmit depolarizing impulses in enteric neurons, thereby enabling the coordination of intestinal motility. However, little is known about the ion channel machinery that specifies firing pattern of enteric neurons. Here, we used in situ patch-clamp recording of myenteric neurons from mice to define functionally the Nav channel subtypes responsible for the electrical signature of myenteric neurons. We found that mouse myenteric neurons exhibit two types of tetrodotoxin-resistant Na(+) currents: an early inactivating Na(+) current (INaT) and a persistent Na(+) current (INaP). INaT was encountered in all myenteric neurons, whereas INaP was preferentially found in Dogiel type II sensory neurons. Knock-out mouse studies, in combination with pharmacological assays, indicate that INaT is carried by the Scn5a-encoded "cardiac" Nav1.5, whereas INaP is attributed to the Scn11a-encoded Nav1.9. Current-clamp experiments show that Nav1.9 flows at subthreshold voltages, generating tonic firing. In addition, action potential (AP) clamp reveals that Nav1.5 contributes to the upstroke velocity of APs, whereas Nav1.9, which remains active during the falling phase, opposes AP repolarization. We developed a computational model of a Dogiel type II myenteric neuron that successfully reproduces all experimentally observed phenomena and highlights the differential roles of Nav1.5 and Nav1.9 in the control of excitability. Our data illustrate how excitability can be finely tuned to provide specific firing templates by the selective deployment of Nav1.5 and Nav1.9 isoforms. We propose that Nav-dependent ENS disorders of excitability may play important roles in the pathogenesis of digestive diseases.
Aix-Marseille-Université, Centre National de la Recherche Scientifique, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Unité Mixte de Recherche 7286, 13344 Marseille France, and International Center for Molecular Physiology (Dnipropetrovsk Division), National Academy of Sciences of Ukraine, 01024 Kiev, Ukraine.
Nancy
N
Osorio
Sergiy
S
Korogod
Patrick
P
Delmas
D000200:Action Potentials; D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009197:Myenteric Plexus / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D062558:NAV1.9 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D062554:NAV1.5 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; C491885:Scn11a protein, mouse; C568321:Scn5a protein, mouse; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin
action potentials; enteric neurons; excitability; gastrointestinal disease; in situ patch clamp; sodium channels