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 (I-NaT) and a persistent Na+ current (I-NaP). I-NaT was encountered in all myenteric neurons, whereas I-NaP was preferentially found in Dogiel type II sensory neurons. Knock-out mouse studies, in combination with pharmacological assays, indicate that I-NaT is carried by the Scn5a-encoded cardiac Nav1.5, whereas I-NaP 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 observedphenomena 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.