title: Low-affinity sulfonylurea binding sites reside on neuronal cell bodies in the brain.
abstract: The antidiabetic sulfonylurea drugs bind to sites associated with an ATP-sensitive potassium (Katp) channel on cell bodies and terminals of neurons which increase their firing rates or transmitter release when glucose concentrations rise or sulfonylureas are present. High-affinity sulfonylurea binding sites are concentrated in areas such as the substantia nigra (SN) where glucose and sulfonylureas increase transmitter release from GABA neurons. But there is a paucity of high-affinity sites in areas such as the hypothalamic ventromedial nucleus (VMN) where many neurons increase their activity when glucose rises. Here we assessed both high- and low--affinity sulfonylurea binding autoradiographically with 20 nM [3H]glyburide in the presence of absence of Gpp(NH)p. Neurotoxin lesions with 6-hydroxydopamine (6-OHDA), 5,7-dihydroxytryptamine (5,7-DHT) and ibotenic acid were used to elucidate the cellular location of the two sites in the VMN, SN and locus coeruleus (LC). In the VMN, 25% of the sites were of low affinity. Neither 6-OHDA nor 5,7-DHT affected [3H]glyburide binding, while ibotenic acid reduced the number of VMN neurons and abolished low-affinity without changing high-affinity binding. In cell-attached patches of isolated VMN neurons, both 10 mM glucose and 100 microM glyburide decreased the open probability of the Katp channel suggesting that the low-affinity binding site resides on these neurons. In the SN pars reticulata, ibotenic acid reduced the number of neurons and high-affinity [3H]glyburide binding was decreased by 20%, while 6-OHDA had no effect. In the SN pars compacta, both 6-OHDA and ibotenic acid destroyed endogenous dopamine neurons and selectivity ablated low-affinity binding. In the LC, 6-OHDA destroyed norepinephrine neurons and abolished low-affinity binding. These data suggest that low-affinity sulfonylurea binding sites reside on cell bodies on VMN, SN dopamine and LC norepinephrine neuron cell bodies and that high-affinity sites may be on axon terminals of GABA neurons in the SN.
authors.affiliation: Neurology Service (127C), DVA Medical Center, E. Orange, Newark, NJ 07103, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Dunn-Meynell
authors.forename: V H
authors.initials: VH
authors.lastname: Routh
authors.forename: J J
authors.initials: JJ
authors.lastname: McArdle
authors.forename: B E
authors.initials: BE
authors.lastname: Levin
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D004594:Electrophysiology; D005905:Glyburide / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018490:Serotonin Agents / Q000633:toxicity; D013453:Sulfonylurea Compounds / Q000378:metabolism*; D013565:Sympatholytics / Q000633:toxicity
chemical_list: D007004:Hypoglycemic Agents; D015221:Potassium Channels; D018490:Serotonin Agents; D013453:Sulfonylurea Compounds; D013565:Sympatholytics; D015116:5,7-Dihydroxytryptamine; D016627:Oxidopamine; D005905:Glyburide