Distinction between adrenergic and serotonergic receptor subtypes: specificity of drugs and absence of cooperative interactions between adrenergic and serotonergic receptor binding sites.
In light of observed amplificatory interactions between serotonergic and adrenergic stimuli in functional studies on vascular tissue and platelets, we investigated the distinction and possible interactions between alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic and 5-HT1A-, 5-HT1B-, and 5-HT2-serotonergic receptor binding sites. Therefore, the binding affinities of archetypes of adrenergic and serotonergic agonists and antagonists for the various receptors were measured. Only the alpha 1-blocker prazosin revealed great specificity for alpha 1-adrenergic receptors; the other investigated antagonists and agonists showed cross-reactivity with adrenergic and serotonergic receptors in various combinations. Using [3H]ketanserin binding to rat frontal cortex and [3H]prazosin binding to rat cortex tissue as models for 5-HT2-serotonergic and alpha 1-adrenergic receptors, respectively, we did not find cooperative effects of epinephrine on the binding of 5-hydroxytryptamine or ketanserin to 5-HT2 receptors nor of 5-hydroxytryptamine on the binding of epinephrine or prazosin to alpha 1-adrenergic receptors. It was concluded that the various adrenergic and serotonergic receptor subtypes (a) have distinct drug binding properties; (b) occur on various central and peripheral tissues; (c) co-occur on some tissues; (d) each subtype mediates several distinct functions; (e) distinct receptors may mediate similar functions; (f) the drug binding properties of a particular receptor remains the same in different tissues, but purported alpha 2-like receptors on platelets reveal some differences from alpha 2-receptors in the brain and other peripheral tissues; (g) the various receptor subtypes appear to be distinct molecular entities; and (h) in brain tissue there is no evidence for the occurrence of direct adrenergic-serotonergic receptor-receptor interactions at the level of the binding sites.
Leysen
J E
JE
Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Van Gompel
P
P
Gommeren
W
W
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004837:Epinephrine / Q000378:metabolism; D011224:Prazosin / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011941:Receptors, Adrenergic / Q000032:analysis / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000032:analysis / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000378:metabolism*; D013566:Sympathomimetics / Q000378:metabolism*
D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013566:Sympathomimetics; D012701:Serotonin; D011224:Prazosin; D004837:Epinephrine