In vivo and in vitro regulation of [3H]glyburide binding to brain sulfonylurea receptors in obesity-prone and resistant rats by glucose.
Select brain neurons increase their firing rate when ambient glucose levels rise, possibly via a neuronal ATP-sensitive K+ (KATP) channel and its associated sulfonylurea receptor (SUR). We used receptor autoradiographic binding of 20 nM [3H]glyburide (in the presence or absence of Gpp(NH)p which blocks binding to low-affinity sites) to assess the in vivo and in vitro effects of altering glucose availability upon high- and low-affinity binding to brain SUR. Since the brain's ability to monitor and regulate glucose metabolism is critical to maintenance of energy balance, testing was done in chow-fed male Sprague-Dawley rats which had an underlying predisposition to develop either diet-induced obesity (DIO-prone) or to be diet-resistant (DR-prone) when subsequently fed a high-energy diet. Under control conditions, both in vivo and in vitro studies showed DIO-prone rats to have reduced levels of low-, but not high-affinity [3H]glyburide binding in most forebrain areas. As compared to equiosmolar infusions of mannitol, 60 min unilateral intracarotid glucose infusions at 4 mg/kg/min in awake rats reduced low-affinity [3H]glyburide binding in numerous hypothalamic and amygdalar areas of both DR- and DIO-prone rats with little effect on high-affinity binding. Only in the paraventricular nucleus of DR-prone rats was there a phenotype-specific downregulation of low-affinity binding. Brain sections from other rats were incubated with [3H]glyburide in the presence of 0, 5 or 10 mM glucose. The resultant in vitro effects of glucose were more variable and widespread than intracarotid infusions. Here, glucose often increased low-affinity [3H]glyburide binding, particularly in DR-prone rats at 5 mM. Again, there was little effect on high-affinity binding. Thus, glucose may affect the firing of glucose-responsive neurons by indirectly altering KATP channel function via its effects on low-affinity cell body SUR.
Levin
B E
BE
Neurology Service (127C), VA Medical Center, E. Orange, NJ 07018, USA. levin@umdnj.edu
Dunn-Meynell
A A
AA
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002339:Carotid Arteries; D004234:Diuretics, Osmotic / Q000494:pharmacology; D002149:Energy Intake; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005905:Glyburide / Q000378:metabolism* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000494:pharmacology; D007269:Injections, Intra-Arterial; D008297:Male; D008353:Mannitol / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism* / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D014316:Tritium
D018528:ATP-Binding Cassette Transporters; D004234:Diuretics, Osmotic; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014316:Tritium; D008353:Mannitol; D005947:Glucose; D005905:Glyburide