RESUMO
The function of the sigma-1 receptor (S1R) has been implicated in modulating the activity of various ion channels. In the CNS S1R is enriched in cholinergic postsynaptic densities in spinal cord motoneurons (MNs). Mutations in S1R have been found in familial cases of amyotrophic lateral sclerosis (ALS). In this study we show that a knockout of S1R in the SOD1*G93A mouse model of ALS significantly reduces longevity (end stage). Electrophysiological experiments demonstrate that MN of mice lacking S1R exhibit increased excitability. Taken together the data suggest the S1R acts as a brake on excitability, an effect that might enhance longevity in an ALS mouse model.
Assuntos
Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Receptores sigma/deficiência , Receptores sigma/genética , Potenciais de Ação/genética , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Biofísica , Modelos Animais de Doenças , Progressão da Doença , Estimulação Elétrica , Proteínas de Fluorescência Verde/genética , Proteínas de Homeodomínio/genética , Técnicas In Vitro , Longevidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-Clamp , Medula Espinal/patologia , Superóxido Dismutase/genética , Natação/psicologia , Fatores de Transcrição/genética , Receptor Sigma-1RESUMO
The function of the sigma-1 receptor (S1R) has been linked to modulating the activities of ion channels and G-protein-coupled receptors (GPCR). In the CNS, the S1R is expressed ubiquitously but is enriched in mouse motoneurons (MN), where it is localized to subsurface cisternae of cholinergic postsynaptic densities, also known as C-terminals. We found that S1R is enriched in mouse spinal MN at late stages of embryonic development when it is first visualized in the endoplasmic reticulum. S1Rs appear to concentrate at C-terminals of mouse MN only on the second week of postnatal development. We found that indole-N-methyl transferase (INMT), an enzyme that converts tryptamine into the sigma-1 ligand dimethyltryptamine (DMT), is also localized to postsynaptic sites of C-terminals in close proximity to the S1R. This close association of INMT and S1Rs suggest that DMT is synthesized locally to effectively activate S1R in MN.
