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101 GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS ACTIVATE ISOLATED NODOSE GANGLION CELLS AND INHIBIT VOLTAGE GATED POTASSIUM CURRENTS G Gaisano, MJ Beyak GLP-1 is well known as an incretin hormone, enhancing glucose stimulated insulin secretion. Recent human and animal studies have indicated that GLP-1 and the GLP-1 agonist, exendin-4, inhibit food intake and result in weight loss, suggesting an important role for GLP-1 in satiety. The satiety actions of GLP-1 are believed to occur through effects on vagal afferents. However the mechanism of action on vagal afferents is unknown.
GIDRU, Queen's University, Kingston, Ontario
AIMS: To characterize the effects of GLP-1 on nodose ganglion neurons, and test the hypothesis that activation of the GLP-1 receptor inhibits voltage gated potassium channels.
METHODS: Nodose ganglia were harvested from male mice, and neurons were dissociated and plated onto glass coverslips. Perforated whole cell patch clamp recordings were performed 24-48 hours later. Responses of the membrane potential to GLP-1 agonists were tested in physiological solutions. Potassium currents resulting from a series of voltage commands were recorded in Na free external solution. Drugs were applied using a fast flow perfusion system. Exendin-4 was used as a GLP-1 agonist.
RESULTS: Exendin-4 (100 nM) depolarized 40% (6/15) of nodose ganglion cells. The mean depolarization was 6.5±.45 mV, and in 2 cells this resulted in spiking. In spontaneously active cells, exendin-4 resulted in a doubling of the firing rate. In voltage clamp recordings, stepwise voltage commands resulted in outward currents with the characteristics of transient Ia and sustained Ik (delayed rectifier) currents. Exendin-4 (100 nM) resulted in a significant suppression of potassium currents in 38% of nodose cells, the effect becoming apparent within 2 minutes, and becoming maximal at 6 minutes. The peak outward current was suppressed by 43±6.5% (p<0.05).
CONCLUSIONS: The GLP-1 agonist results in depolarization of a subpopulation of mouse nodose ganglion neurons. This increased firing frequency or resulted in spiking in some cells. Mouse nodose ganglion neurons express Ia and Ik like voltage gated potassium currents. Voltage gated potassium currents were suppressed by GLP-1. As potassium currents are a major mechanism limiting neuronal excitability, suppression of voltage gated potassium currents is a likely mechanism by which GLP-1 increases vagal afferent activity, and therefore a mechanism by which GLP-1 limits food intake.