title: Kinetic evidence for different mechanisms of interaction of black mamba toxins MT alpha and MT beta with muscarinic receptors.
abstract: By studying the influence of two toxins from the black mamba Dendroaspis polylepis on the kinetics of [3H]-N-methylscopolamine binding to muscarinic acetylcholine receptors from rat cerebral cortex, it was revealed that these toxins, MT alpha and MT beta, interact with the receptors via kinetically distinct mechanisms. MT beta bound to receptors in a one-step, readily reversible process with the dissociation constant K(d)=5.3 microM. The binding mechanism of MTalpha was more complex, involving at least two consecutive steps. A fast receptor-toxin complex formation (K(T)=3.8 microM) was followed by a slow process of isomerisation of this complex (k(i)=1.8 x 10(-2) s(-1), half-time 39 s). A similar two-step interaction mechanism has been established for a related toxin, MT2 from the green mamba D. angusticeps (K(T)=1.4 microM, k(i)=8.3 x 10(-4) s(-1), half-time 840 s). The slow isomerisation process delays the effect of MT alpha and MT2, but increases their apparent potency compared to toxins unable to induce the isomerisation process.
authors.affiliation: Department of Physiology, Biomedical Centre, Uppsala University, Sweden. mikael.jolkkonen@fysiologi.uu.se
authors.forename: M
authors.initials: M
authors.lastname: Jolkkonen
authors.forename: A
authors.initials: A
authors.lastname: Oras
authors.forename: T
authors.initials: T
authors.lastname: Toomela
authors.forename: E
authors.initials: E
authors.lastname: Karlsson
authors.forename: J
authors.initials: J
authors.lastname: Järv
authors.forename: K E
authors.initials: KE
authors.lastname: Akerman
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004546:Elapid Venoms / Q000378:metabolism* / Q000633:toxicity*; D017815:Elapidae; D007700:Kinetics; D019832:N-Methylscopolamine / Q000378:metabolism* / Q000493:pharmacokinetics; D010276:Parasympatholytics / Q000378:metabolism* / Q000493:pharmacokinetics; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism
chemical_list: D004546:Elapid Venoms; D010276:Parasympatholytics; D011976:Receptors, Muscarinic; D019832:N-Methylscopolamine