Activation and inhibition of native neuronal alpha-bungarotoxin-sensitive nicotinic ACh receptors.
Tuberomammillary histamine neurons (TM) of the posterior hypothalamus exclusively express alpha-bungarotoxin (alphaBgt) sensitive nicotinic receptors, providing a unique model system for studying physiological properties of native alpha7-like receptors. Here the properties of alphaBgt-sensitive receptors were investigated using the patch-clamp technique and rapid application of acetylcholine (ACh) or the alpha7-selective agonists, 3-(4-hydroxy,2-methoxybenzylidene)anabaseine (4OH-GTS-21), and choline. Alpha-Bgt-sensitive receptor responses to rapid application of high agonist concentrations were characterized by a transient current which rapidly decayed in a voltage-independent concentration-dependent manner to a relatively sustained slow current. Upon agonist removal, current persisted for several milliseconds (or longer) and increased above the level of the slow current (rebound). Lower agonist concentrations did not produce a rebound. Our analysis suggests that the current rebound represents a recovery phase from a low potency inhibition. This inhibition was voltage-dependent for ACh and choline but voltage-independent for 4OH-GTS-21. A slow form of desensitization was present which was relatively agonist-independent and was faster than the rate of 4OH-GTS-21 unbinding. Kinetic analysis revealed that the concentration dependence of the transient response amplitudes was compromised by solution exchange; net charge measurements over the late response phases were chosen as an alternative measure of concentration/response function. Our data suggest that low agonist concentrations can evoke a prolonged or tonic-like receptor activation. Functioning in this modality, receptors would regulate calcium homeostasis over a narrow, but therapeutically important, range of intracellular calcium concentrations. This could then provide the basis for cytoprotective effects of 4OH-GTS-21 and other nicotinic agonists, mediating trophic and neuromodulatory functions.
Uteshev
Vladimir V
VV
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Box 100267 JHMHSC, 1600 SW Archer Rd, University of Florida, Gainesville 32610-0267, FL, USA.
Meyer
Edwin M
EM
Papke
Roger L
RL
D000109:Acetylcholine / Q000494:pharmacology; D000691:Anabasine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology*; D002794:Choline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000166:cytology; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
C116666:3-(4-hydroxy-2-methoxybenzylidene)anabaseine; D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D006632:Histamine; D000691:Anabasine; D002794:Choline; D000109:Acetylcholine