Mutual interactions of the presynaptic histamine H3 and prostaglandin EP3 receptors on the noradrenergic terminals in the mouse brain.
We studied whether interactions between the presynaptic histamine H3 and prostaglandin EP3 receptors on the noradrenergic neurons of the mouse brain cortex occur. Cerebral cortex slices from the mouse (and, in few experiments, from the rat) were preincubated with [3H]noradrenaline and then superfused with a physiological salt solution. Tritium overflow was evoked electrically, either at 0.3 or 3 Hz (2 min) (standard stimulation protocol) or at 100 Hz (eight pulses) (stimulation protocol under which almost no activation of the presynaptic alpha2-adrenoceptors by endogenous noradrenaline occurs). In another set of experiments, Ca2+ ions were introduced into Ca2+-free K+-rich medium containing tetrodotoxin to evoke tritium overflow. The electrically-evoked tritium overflow (0.3 Hz) was inhibited by histamine or the H3 receptor agonist imetit, acting via H3 receptors. and by prostaglandin E2 or the EP3 receptor agonist sulprostone, acting via EP3 receptors. When histamine or imetit was given first (at concentrations causing the maximum effect at H3 receptors), the effect of prostaglandin E2 on the evoked tritium overflow was attenuated by 5-10%. When prostaglandin E2 or sulprostone was given first (at concentrations causing the maximum effect at EP3 receptors), the effect of histamine or imetit on the evoked overflow was attenuated by almost 50%. The previous administration of prostaglandin E2 also blunted the effect of histamine on the evoked tritium overflow evoked at 3 Hz; the degree of attenuation was identical when the current strength was 25 mA or was increased to 100 or 200 mA in order to partially compensate for the inhibitory effect of prostaglandin E2 on the evoked overflow. In addition, prostaglandin E2 attenuated the effect of histamine when tritium overflow was evoked (i) by 100 Hz, eight pulses or (ii) by Ca2+ ions or (iii) when rat (instead of mouse) brain cortex slices were used. An interaction of prostaglandin E2 or sulprostone with the H3 receptor recognition site could be excluded since both prostanoids did not affect the specific binding of the H3 agonist radioligand [3H]N(alpha)-methylhistamine to rat brain cortex membranes. In conclusion, mutual interactions occur between the presynaptic H3 and EP3 receptors involved in the inhibition of noradrenaline release in the mouse brain cortex. Pre-activation of the H3 receptor slightly attenuates the EP3 receptor-mediated effect whereas pre-activation of the EP3 receptor more markedly attenuates the H3 receptor-mediated effect. The interactions may occur between the receptors themselves or at a step behind the receptors (e.g., at the level of G proteins). The physiological significance of these interactions may be to limit the total extent of inhibition of noradrenaline release in a scenario under which both receptors are activated simultaneously.
Schlicker
E
E
Institut für Pharmakologie und Toxikologie, Universität Bonn, Germany.
Marr
I
I
D000818:Animals; D001921:Brain / Q000502:physiology*; D002118:Calcium / Q000494:pharmacology; D002540:Cerebral Cortex / Q000502:physiology*; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009411:Nerve Endings / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000378:metabolism*; D011865:Radioisotope Dilution Technique; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology; D018100:Receptors, Histamine H3 / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014316:Tritium
D017442:Histamine Agonists; D007093:Imidazoles; C545648:Ptger3 protein, mouse; C545649:Ptger3 protein, rat; D018341:Receptors, Adrenergic, alpha-2; D018100:Receptors, Histamine H3; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014316:Tritium; C016767:sulprostone; C077430:imetit; D006632:Histamine; D013890:Thiourea; D015232:Dinoprostone; D002118:Calcium; D009638:Norepinephrine