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Hypothalamic Proopiomelanocortin Neurons Are Glucose Responsive and Express K_ATP Channels

Department of Physiology and Pharmacology (N.I., M.A.B., J.Q., O.K.R., M.J.K.), The Vollum Institute (J.L.S., M.J.L.), and Department of Behavioral Neuroscience (M.J.L.), Oregon National Primate Research Center (O.K.R.), Oregon Health & Science University, Portland, Oregon 97239-3098; and Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (M.R.), Consejo Nacional de Investigaciones Científicas y Técnicas, and Department of Biology, School of Sciences, University of Buenos Aires, Buenos Aires, Argentina

Address all correspondence and requests for reprints to: Martin J. Kelly, Ph.D., Department of Physiology and Pharmacology, L334, Oregon Health Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239-3098. E-mail: kellym{at}ohsu.edu.

Hypothalamic proopiomelanocortin (POMC) neurons are critical for controlling homeostatic functions in the mammal. We used a transgenic mouse model in which the POMC neurons were labeled with enhanced green fluorescent protein to perform visualized, whole-cell patch recordings from prepubertal female hypothalamic slices. The mouse POMC-enhanced green fluorescent protein neurons expressed the same endogenous conductances (a transient outward K⁺ current and a hyperpolarization-activated, cation current) that have been described for guinea pig POMC neurons. In addition, the selective µ-opioid receptor agonist DAMGO induced an outward current (maximum of 12.8 ± 1.2 pA), which reversed at K⁺ equilibrium potential (E_K+), in the majority (85%) of POMC neurons with an EC₅₀ of 102 nM. This response was blocked by the opioid receptor antagonist naloxone with an inhibition constant of 3.1 nM. In addition, the -aminobutyric acid_B receptor agonist baclofen (40 µM) caused an outward current (21.6 ± 4.0 pA) that reversed at E_K+ in these same neurons. The ATP-sensitive potassium channel opener diazoxide also induced an outward K⁺ current (maximum of 18.7 ± 2.2 pA) in the majority (92%) of POMC neurons with an EC₅₀ of 61 µM. The response to diazoxide was blocked by the sulfonylurea tolbutamide, indicating that the POMC neurons express both Kir6.2 and sulfonylurea receptor 1 channel subunits, which was verified using single cell RT-PCR. This pharmacological and molecular profile suggested that POMC neurons might be sensitive to metabolic inhibition, and indeed, we found that their firing rate varied with changes in glucose concentrations. Therefore, it appears that POMC neurons may function as an integrator of metabolic cues and synaptic input for controlling homeostasis in the mammal.

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