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incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel.

Title: The incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel.
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Name(s): Thiebaud, Nicolas, author
Llewellyn-Smith, Ida J, author
Gribble, Fiona, author
Reimann, Frank, author
Trapp, Stefan, author
Fadool, Debra Ann, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2016-05-15
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: The gut hormone called glucagon-like peptide 1 (GLP-1) is a strong moderator of energy homeostasis and communication between the peripheral organs and the brain. GLP-1 signalling occurs in the brain; using a newly developed genetic reporter line of mice, we have discovered GLP-synthesizing cells in the olfactory bulb. GLP-1 increases the firing frequency of neurons (mitral cells) that encode olfactory information by decreasing activity of voltage-dependent K channels (Kv1.3). Modifying GLP-1 levels, either therapeutically or following the ingestion of food, could alter the excitability of neurons in the olfactory bulb in a nutrition or energy state-dependent manner to influence olfactory detection or metabolic sensing. The results of the present study uncover a new function for an olfactory bulb neuron (deep short axon cells, Cajal cells) that could be capable of modifying mitral cell activity through the release of GLP-1. This might be of relevance for the action of GLP-1 mimetics now widely used in the treatment of diabetes. The olfactory system is intricately linked with the endocrine system where it may serve as a detector of the internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU-yellow fluorescent protein mice that express a genetic reporter under the control of the preproglucagon reporter suggested the presence of the gut hormone, glucagon-like peptide (GLP-1), in deep short axon cells (Cajal cells) of the olfactory bulb and its neuromodulatory effect on mitral cell (MC) first-order neurons. A MC target for the peptide was determined using GLP-1 receptor binding assays, immunocytochemistry for the receptor and injection of fluorescence-labelled GLP-1 analogue exendin-4. Using patch clamp recording of olfactory bulb slices in the whole-cell configuration, we report that GLP-1 and its stable analogue exendin-4 increase the action potential firing frequency of MCs by decreasing the interburst interval rather than modifying the action potential shape, train length or interspike interval. GLP-1 decreases Kv1.3 channel contribution to outward currents in voltage clamp recordings as determined by pharmacological blockade of Kv1.3 or utilizing mice with Kv1.3 gene-targeted deletion as a negative control. Because fluctuations in GLP-1 concentrations monitored by the olfactory bulb can modify the firing frequency of MCs, olfactory coding could change depending upon nutritional or physiological state. As a regulator of neuronal activity, GLP-1 or its analogue may comprise a new metabolic factor with a potential therapeutic target in the olfactory bulb (i.e. via intranasal delivery) for controlling an imbalance in energy homeostasis.
Identifier: FSU_pmch_26931093 (IID), 10.1113/JP272322 (DOI), PMC4865572 (PMCID), 26931093 (RID), 26931093 (EID)
Grant Number: MC_UU_12012/3, R01 DC013080, MR/J013293/2, MR/J013293/1, R03 DC013988,
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865572.
Subject(s): Action Potentials/drug effects
Action Potentials/physiology
Animals
Dose-Response Relationship, Drug
Female
Glucagon-Like Peptide 1/pharmacology
Glucagon-Like Peptide-1 Receptor/deficiency
Incretins/pharmacology
Kv1.3 Potassium Channel/deficiency
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Olfactory Bulb/cytology
Olfactory Bulb/drug effects
Olfactory Bulb/physiology
Organ Culture Techniques
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_26931093
Owner Institution: FSU
Is Part Of: The Journal of physiology.
1469-7793
Issue: iss. 10, vol. 594

Choose the citation style.
Thiebaud, N., Llewellyn-Smith, I. J., Gribble, F., Reimann, F., Trapp, S., & Fadool, D. A. (2016). The incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel. The Journal Of Physiology. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_26931093