Small-conductance Ca(2+)-activated K(+) channels: Heterogeneous affinity in rat brain structures and cognitive modulation by specific blockers.
Small-conductance calcium-activated potassium channels (K(Ca)2) generating the medium afterhyperpolarization seen after an action potential modulate the neuronal integration signal. The effects of two K(Ca)2 channel blockers, apamin, specific to K(Ca)2.2 and K(Ca)2.3 channels, and lei-Dab7, which binds to K(Ca)2.2 channels only, were compared to evaluate the involvement of K(Ca)2 channel subunits in behavior, spatial learning and memory in rats. Intracerebroventricular (9-5 ng) injections of lei-dab7 decreased locomotor activity, food intake and body weight in rats deprived of food. A dose of 3 ng lei-Dab7 had no effect on these types of behavior. We therefore used this dose for attention and memory tasks. No modification to attention or memory was observed in a spatial radial-arm maze task with rats given 3 ng lei-Dab7, whereas apamin (0.3 ng) improved reference memory and accelerated changes of strategy from egocentric to allocentric. These findings suggest that K(Ca)2.3 blockade improves memory in rats. Lei-Dab7 entirely outcompeted the binding of iodinated apamin to 64 brain structures (mean IC(50): 34.5 nM), although IC(50) values were highly variable. By contrast, overall IC(50) values for apamin were close to mean values (11.3 pM). The very low affinity of the hippocampus and neocortex for lei-Dab7 may account for the absence of a behavioral effect of this compound. The variability of IC(50) values suggests that K(Ca)2 channel composition varies considerably as a function of the brain structure considered.
Mpari
Bedel
B
Laboratoire de Neurobiologie Intégrative et Adaptative, Neurobiologie des Processus Mnésiques, UMR 6149, CNRS-Université de Provence, Centre St Charles, Marseille Cedex 03, France.
Sreng
Leam
L
Regaya
Imed
I
Mourre
Christiane
C
D000818:Animals; D001030:Apamin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001288:Attention / Q000187:drug effects; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D007276:Injections, Intraventricular; D007457:Iodine Radioisotopes; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012604:Scorpion Venoms / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007457:Iodine Radioisotopes; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms; D051640:Small-Conductance Calcium-Activated Potassium Channels; C442227:diaminobutanoyl(7)-leiurotoxin I; D001030:Apamin