Publicação
The role of adenosine A2A receptors on neuromuscular transmission upon ageing
| Resumo: | Adenosine is a neuromodulator with important actions in the nervous system. The activation of adenosine A2A receptors has been shown to modulate the action of other receptors. Considering that it was observed an interaction between adenosine A2A receptors and TrkB receptors in hippocampus, I hypothesized that the activation of A2A receptors could also facilitate BDNF actions on neuromuscular transmission. To answer that question I performed intracellular electrophysiological recordings in isolated preparations of the phrenic-nerve diaphragm from male infant rats. The data herein described clearly shows that there is a crosstalk between A2A receptors and TrkB receptors at the neuromuscular junction, where A2A receptors trigger the excitatory action of BDNF on neuromuscular transmission, through a mechanism that involves PLCy. When I was investigating the interaction between adenosine A2A receptors and TrkB receptors on neuromuscular transmission, I induced the increase of the endogenous adenosine level at the synaptic cleft, with an adenosine kinase inhibitor, 5`-iodotubericidin (ITU). It was observed that instead of inhibition, ITU greatly facilitated neuromuscular transmission. It was the first time that an excitatory effect induced by endogenous adenosine, at low frequency stimulation, was observed. Therefore I considered of interest to study the balance between adenosine A1 and A2A receptors at the neuromuscular junction upon ageing, since the activation of adenosine A2A receptors has been shown to influence the actions of adenosine A1 receptors and no one had looked at the excitatory actions of adenosine in aged rats at the neuromuscular junction. I performed intracellular electrophysiological experiments in isolated preparations of the phrenic-nerve diaphragm from four groups of male rats, with different ages: infant (3-4 weeks old), young adult (12-16 weeks old), older adult (36-40 weeks old) and aged (70-80 weeks old). The data herein reported clearly showed that there is a predominance of excitatory adenosine effects at the motor nerve endings of infant rats. Moreover, ageing influenced adenosine A1 and A2A receptors, at the motor nerve terminals, in a different manner. The actions of A2A receptors decreased with ageing, even disappearing in aged rats, whereas the actions of A1 receptors remained unchanged upon ageing. Furthermore, the actions of adenosine A2A receptors on neuromuscular transmission are dependent on adenosine A1 receptors activation, since the excitatory effect of A2A receptors was prevented by the adenosine A1 receptor antagonist. In conclusion, the data presented here demonstrate that adenosine A2A receptors play a crucial role at the neuromuscular junction, since their effects on neuromuscular transmission predominate over adenosine A1 receptors, in infant rats, and the excitatory effect of BDNF on neuromuscular transmission is dependent on their activation. The absence of adenosine A2A receptors effects in aged rats might be one of the causes of the neuromuscular transmission impairment. The results herein described are relevant for a better understanding on the role of adenosine at the neuromuscular junction upon ageing, opening novel scientific questions such as investigate the role of adenosine A2A receptors on neuromuscular transmission in the cenarios of neuromuscular disease as, for example, the amyotrophic lateral sclerosis disease. |
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| Autores principais: | Pousinha, Paula Isabel Antunes, 1978- |
| Assunto: | Adenosina Receptor A2A de adenosina Envelhecimento Manifestações neuromusculares Teses de doutoramento - 2012 |
| Ano: | 2012 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Adenosine is a neuromodulator with important actions in the nervous system. The activation of adenosine A2A receptors has been shown to modulate the action of other receptors. Considering that it was observed an interaction between adenosine A2A receptors and TrkB receptors in hippocampus, I hypothesized that the activation of A2A receptors could also facilitate BDNF actions on neuromuscular transmission. To answer that question I performed intracellular electrophysiological recordings in isolated preparations of the phrenic-nerve diaphragm from male infant rats. The data herein described clearly shows that there is a crosstalk between A2A receptors and TrkB receptors at the neuromuscular junction, where A2A receptors trigger the excitatory action of BDNF on neuromuscular transmission, through a mechanism that involves PLCy. When I was investigating the interaction between adenosine A2A receptors and TrkB receptors on neuromuscular transmission, I induced the increase of the endogenous adenosine level at the synaptic cleft, with an adenosine kinase inhibitor, 5`-iodotubericidin (ITU). It was observed that instead of inhibition, ITU greatly facilitated neuromuscular transmission. It was the first time that an excitatory effect induced by endogenous adenosine, at low frequency stimulation, was observed. Therefore I considered of interest to study the balance between adenosine A1 and A2A receptors at the neuromuscular junction upon ageing, since the activation of adenosine A2A receptors has been shown to influence the actions of adenosine A1 receptors and no one had looked at the excitatory actions of adenosine in aged rats at the neuromuscular junction. I performed intracellular electrophysiological experiments in isolated preparations of the phrenic-nerve diaphragm from four groups of male rats, with different ages: infant (3-4 weeks old), young adult (12-16 weeks old), older adult (36-40 weeks old) and aged (70-80 weeks old). The data herein reported clearly showed that there is a predominance of excitatory adenosine effects at the motor nerve endings of infant rats. Moreover, ageing influenced adenosine A1 and A2A receptors, at the motor nerve terminals, in a different manner. The actions of A2A receptors decreased with ageing, even disappearing in aged rats, whereas the actions of A1 receptors remained unchanged upon ageing. Furthermore, the actions of adenosine A2A receptors on neuromuscular transmission are dependent on adenosine A1 receptors activation, since the excitatory effect of A2A receptors was prevented by the adenosine A1 receptor antagonist. In conclusion, the data presented here demonstrate that adenosine A2A receptors play a crucial role at the neuromuscular junction, since their effects on neuromuscular transmission predominate over adenosine A1 receptors, in infant rats, and the excitatory effect of BDNF on neuromuscular transmission is dependent on their activation. The absence of adenosine A2A receptors effects in aged rats might be one of the causes of the neuromuscular transmission impairment. The results herein described are relevant for a better understanding on the role of adenosine at the neuromuscular junction upon ageing, opening novel scientific questions such as investigate the role of adenosine A2A receptors on neuromuscular transmission in the cenarios of neuromuscular disease as, for example, the amyotrophic lateral sclerosis disease. |
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