Glucagon-like peptide-1 inhibits voltage-gated potassium currents in mouse nodose ganglion neurons

Abstract

Background  Glucagon-like peptide-1 (GLP-1) is a major hormone known to regulate glucose homeostasis and gut function, and is an important satiety mediator. These actions are at least in part mediated via an action on vagal afferent neurons. However, the mechanism by which GLP-1 activates vagal afferents remains unknown. We hypothesized that GLP-1 acts on nodose ganglion neuron voltage-gated potassium (KV) channels, increasing membrane excitability.

Methods  Employing perforated patch clamp recordings we examined the effects of GLP-1 on membrane properties as well as voltage-gated potassium currents. Extracellular recordings of jejunal afferents were performed to demonstrate the functional relevance of these effects at the nerve terminal.

Key Results  Glucagon-like peptide-1 depolarized a subpopulation of nodose neurons. This membrane depolarization was used to identify neurons containing functional GLP-1 receptors. In these neurons, GLP-1 decreased rheobase and broadened the action potential, and increased the number of action potentials elicited at twice rheobase. We identified a GLP-1 sensitive current whose reversal potential shifted in a depolarizing direction when extracellular potassium was increased. We identified two macroscopic K currents, IA, an inactivating current and IK a sustained current. GLP-1 caused inhibition of these currents, IK by 45%, P < 0.05 and IA currents by 52%P < 0.01, associated with a hyperpolarizing shift of steady-state inactivation curves for both currents. In extracellular recordings of jejunal afferents, GLP-1 increased firing rate, the effect blocked by the K+ channel antagonist 4-AP.

Conclusions & Inferences  These experiments indicate that GLP-1 receptor activation results in vagal afferent excitation, due at least in part to inhibition of sustained and inactivating potassium currents. This mechanism may be important in satiety and glucose homeostatic signals arising from the gastrointestinal tract.