title: The interaction between tropomyosin-related kinase B receptors and presynaptic muscarinic receptors modulates transmitter release in adult rodent motor nerve terminals.
abstract: The neurotrophin brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4) and the receptors tropomyosin-related kinase B (trkB) and p75(NTR) are present in the nerve terminals on the neuromuscular junctions (NMJs) of the levator auris longus muscle of the adult mouse. Exogenously added BDNF or NT-4 increased evoked ACh release after 3 h. This presynaptic effect (the size of the spontaneous potentials is not affected) is specific because it is not produced by neurotrophin-3 (NT-3) and is prevented by preincubation with trkB-IgG chimera or by pharmacological block of trkB [K-252a (C₂₇H₂₁N₃O₅)] or p75(NTR) [Pep5 (C₈₆H₁₁₁N₂₅O₁₉S₂] signaling. The effect of BDNF depends on the M₁ and M₂ muscarinic acetylcholine autoreceptors (mAChRs) because it is prevented by atropine, pirenzepine and methoctramine. We found that K-252a incubation reduces ACh release (~50%) in a short time (1 h), but the p75(NTR) signaling inhibitor Pep5 does not have this effect. The specificity of the K-252a blocking effect on trkB was confirmed with the anti-trkB antibody 47/trkB, which reduces evoked ACh release, like K-252a, whereas the nonpermeant tyrosine kinase blocker K-252b does not. Neither does incubation with the fusion protein trkB-IgG (to chelate endogenous BDNF/NT-4), anti-BDNF or anti-NT-4 change ACh release. Thus, the trkB receptor normally seems to be coupled to ACh release when there is no short-term local effect of neurotrophins at the NMJ. The normal function of the mAChR mechanism is a permissive prerequisite for the trkB pathway to couple to ACh release. Reciprocally, the normal function of trkB modulates M₁- and M₂-subtype muscarinic pathways.
authors.affiliation: Unitat d'Histologia i Neurobiologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, 43201 Reus, Spain. nsg@fmcs.urv.es
authors.forename: Neus
authors.initials: N
authors.lastname: Garcia
authors.forename: Marta
authors.initials: M
authors.lastname: Tomàs
authors.forename: Manel M
authors.initials: MM
authors.lastname: Santafé
authors.forename: Nuria
authors.initials: N
authors.lastname: Besalduch
authors.forename: Maria A
authors.initials: MA
authors.lastname: Lanuza
authors.forename: Josep
authors.initials: J
authors.lastname: Tomàs
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology; D002038:Bungarotoxins / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D026121:Indole Alkaloids / Q000494:pharmacology; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000166:cytology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010890:Pirenzepine / Q000494:pharmacology; D050765:Qa-SNARE Proteins / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002038:Bungarotoxins; D002227:Carbazoles; D003959:Diamines; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D018727:Muscarinic Antagonists; D009414:Nerve Growth Factors; D018377:Neurotransmitter Agents; D050765:Qa-SNARE Proteins; D020800:Receptor, Nerve Growth Factor; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D001285:Atropine; C049985:staurosporine aglycone; D020813:Receptor, trkB; D000109:Acetylcholine; C054938:methoctramine; C073922:neurotrophin 4