The interaction between tropomyosin-related kinase B receptors and serine kinases modulates acetylcholine release in adult neuromuscular junctions
Graphical abstract
Introduction
Several signaling mediators and their receptors transmit information between the cells that make up the synapses (pre- and postsynaptic cells and glia). In the neuromuscular synapses on the skeletal muscles, several subtypes of presynaptic muscarinic acetylcholine autoreceptors (mAChRs) [4], [16], [24], [25], adenosine receptors [26] and neurotrophin receptors [2], [17], [18], among others, cooperate to control the functional conditions of transmitter release in response to variable activity demands. These metabotropic receptors are coupled to a limited repertoire of presynaptic effector kinases which finally phosphorylate proteins and regulate neurotransmitter release.
In previous studies, we found that the muscarinic mechanism strongly influences serine-threonine kinase activity, both protein kinase C (PKC) and protein kinase A (PKA) [20], [23]. M1 and M2 subtypes of muscarinic receptors were involved in enhancing and inhibiting ACh release, respectively. Also, PKA (but not PKC) plays a constitutive role in promoting a component of normal release. The selective block of M1 or M2 inverts this kinase function: PKC can then stimulate transmitter release, whereas PKA is uncoupled [21]. Here, we use electrophysiological techniques to investigate the functional interactions between the neurotrophin receptor tropomyosin-related kinase B (trkB) receptor, which binds the target-derived brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4) [8], and the serine-threonine kinases PKC and PKA and to demonstrate their coordinated role in transmitter release.
It is generally believed that neurotrophin receptors promote local acute effects in nerve endings, and retrograde long-term effects in distant neuronal cell bodies [6], [7], [9], [11], [13], [14]. Here we analyzed the acute effect on transmitter release resulting from changes in trkB and serine kinases.
Section snippets
Animals
Experiments were performed on the Levator auris longus (LAL) muscle of adult male Swiss mice (30–40 days postnatal; Criffa, Barcelona, Spain). The animals were anesthetized with 2% tribromoethanol (0.15 ml/10 g body weight, I.P.) and killed by exanguination while deeply anesthetized. The total number of mice studied was 95. The animals were cared for in accordance with the guidelines of the European Community's Council Directive of 24 November 1986 (86/609/EEC) for the humane treatment of
Results and discussion
In a previous study [8], we found that exogenously added BDNF (10 nM) potentiates evoked ACh release in a trkB and p75NTR receptor dependent manner because potentiation is prevented by the pharmacological block of trkB (K-252a, 200 nM, 1 h) or p75NTR (Pep5, 1 μM, 1 h). The inhibition of the trkB receptor with K-252a does not merely prevent the effect of exogenous BDNF, but also gives rise by itself to a significant reduction in the size of EPPs (∼50%) after one hour of incubation (Fig. 1, Fig. 2,
Acknowledgements
This work was supported by a grant from MEC (SAF2011-23711) and a grant from the Catalan Government (Generalitat) (2009SGR01248).
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These authors contributed equally to this work.