The ALS-Related o1R E102Q Mutant Eludes Ligand Control and Exhibits Anomalous Response to Calcium
Sigma receptor type 1 (o1R) is a transmembrane protein expressed throughout the central nervous system and in certain peripheral tissues. The human o1R E102Q mutation causes juvenile amyotrophic lateral sclerosis (ALS), likely by inducing a series of alterations in calcium efflux from the endoplasmi...
| Autores: | , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/238822 |
| Acceso en línea: | http://hdl.handle.net/10261/238822 |
| Access Level: | acceso abierto |
| Palabra clave: | sigma type receptor 1 juvenile amyotrophic lateral sclerosis E102Q mutation N-methyl-D-aspartate receptor transient receptor potential calcium channels binding immunoglobulin protein |
| Sumario: | Sigma receptor type 1 (o1R) is a transmembrane protein expressed throughout the central nervous system and in certain peripheral tissues. The human o1R E102Q mutation causes juvenile amyotrophic lateral sclerosis (ALS), likely by inducing a series of alterations in calcium efflux from the endoplasmic reticulum (ER) to mitochondria that affects calcium homeostasis and cellular survival. Here, we report the influence of calcium on o1R E102Q associations with glutamate N-methyl-D-aspartate receptors (NMDARs), binding immunoglobulin protein (BiP), and transient receptor potential calcium channels A1, V1, and M8. The mutant protein inhibited the binding of calmodulin to these calcium channels and interacted less with BiP than wild-type o1R, thereby contributing to calcium homeostasis dysfunction. Mutant o1R, but not wild-type o1R, strongly bound to histidine triad nucleotide binding protein 1, which regulates neuromuscular synaptic organization and target selection through teneurin 1. While ligands regulated the association of o1R wild-type with NMDARs and BiP, they failed to modulate the interaction between these proteins and the o1R E102Q mutant. Thus, the o1R E102Q mutant exhibited an anomalous response to cytosolic calcium levels, altered affinity for target proteins, and a loss of response to regulatory ligands. We believe that these modifications may contribute to the onset of juvenile ALS. |
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