The ALS-related ?1R E102Q Mutant Eludes Ligand Control and Exhibits Anomalous Response to Calcium.

ABSTRACT: Sigma receptor type 1 (?1R) is a transmembrane protein expressed throughout the central nervous system and in certain peripheral tissues. The human ?1R 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 ?1R 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 ?1R, thereby contributing to calcium homeostasis dysfunction. Mutant ?1R, but not wild-type ?1R, 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 ?1R wild-type with NMDARs and BiP, they failed to modulate the interaction between these proteins and the ?1R E102Q mutant. Thus, the ?1R 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.

SUBMITTER: Rodriguez-Munoz M 

PROVIDER: S-EPMC7582951 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature