Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine

Adith S. Arun, Chelsy R. Eddings, Katherine Lee Wilson

Research output: Contribution to journalArticle

Abstract

Sigma-1 receptor (Sigma1R; SIGMAR1), an integral membrane protein of the endoplasmic reticulum and nuclear envelope, has a hydrophobic drug-binding pocket that binds with high affinity to addictive drugs (cocaine, methamphetamine) and therapeutics used to treat a wide spectrum of neurological disorders. Cocaine enhances Sigma1R association with three nuclear lamina proteins (emerin, lamin A/C, BANF1), causing Sigma1R-dependent and emerin-dependent recruitment and transcriptional repression of a gene, MAOB1, involved in dopamine removal from neural synapses. The mechanism of Sigma1R association with emerin and the molecular impact of cocaine on their association are unknown. Mutations in Sigma1R, as a proposed regulator or mis-regulator of the nuclear lamina, have the potential to alter nuclear lamina function in brain or other tissues. We examined the frequency of SIGMAR1 missense alleles among 60,706 unrelated individuals in the ExAC database. We identified two novel SIGMAR1 missense variants of particular interest due to their frequency and potential to impact molecular association with emerin or other nuclear lamina proteins. Variant p.Q2P was widespread in ExAC (overall allele frequency 18.4%) with broad ethnic distribution among non-Finnish Europeans, Africans, South Asians, Latinx (allele frequencies ∼15% to 23%), and East Asians (∼38%). The p.R208W allele was identified in ∼0.78% of individuals overall with enrichment in Africans, Latinx, and East Asians (∼1.9–2.9%). These and other novel Sigma1R variants provide tools for future studies to determine the molecular basis of Sigma1R association with emerin and the mechanism of nuclear lamina misregulation by cocaine and potentially other Sigma1R agonists. Impact statement: The Sigma-1 Receptor (Sigma1R; SIGMAR1) binds neuroactive drugs—both therapeutic and addictive—and associates with the nuclear membrane protein emerin and its partners lamin A/C and BANF1 in response to cocaine, through unknown mechanisms. We identified two novel SIGMAR1 missense variants of special interest due to their prevalence in human populations and their potential to perturb Sigma1R function at the nuclear envelope. Despite its importance in physiology and pharmacology, many aspects of Sigma1R including its membrane topology are unclear. Our findings lay the foundation for future molecular studies to understand how Sigma1R associates with emerin, lamin A/C, and BANF1 and manipulates their activity in response to agonist.

Original languageEnglish (US)
JournalExperimental Biology and Medicine
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Gene Silencing
Nuclear Lamina
Cocaine
Genes
Alleles
Lamin Type A
Nuclear Envelope
Nuclear Proteins
Gene Frequency
Membrane Proteins
Methamphetamine
Physiology
emerin
Nervous System Diseases
Endoplasmic Reticulum
Pharmaceutical Preparations
Synapses
Dopamine
Brain
Proteins

Keywords

  • BANF1
  • cocaine
  • Emerin
  • LMNA
  • nuclear lamina
  • Sigma-1 receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

@article{72949930df544d039b8c57e54eff10fa,
title = "Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine",
abstract = "Sigma-1 receptor (Sigma1R; SIGMAR1), an integral membrane protein of the endoplasmic reticulum and nuclear envelope, has a hydrophobic drug-binding pocket that binds with high affinity to addictive drugs (cocaine, methamphetamine) and therapeutics used to treat a wide spectrum of neurological disorders. Cocaine enhances Sigma1R association with three nuclear lamina proteins (emerin, lamin A/C, BANF1), causing Sigma1R-dependent and emerin-dependent recruitment and transcriptional repression of a gene, MAOB1, involved in dopamine removal from neural synapses. The mechanism of Sigma1R association with emerin and the molecular impact of cocaine on their association are unknown. Mutations in Sigma1R, as a proposed regulator or mis-regulator of the nuclear lamina, have the potential to alter nuclear lamina function in brain or other tissues. We examined the frequency of SIGMAR1 missense alleles among 60,706 unrelated individuals in the ExAC database. We identified two novel SIGMAR1 missense variants of particular interest due to their frequency and potential to impact molecular association with emerin or other nuclear lamina proteins. Variant p.Q2P was widespread in ExAC (overall allele frequency 18.4{\%}) with broad ethnic distribution among non-Finnish Europeans, Africans, South Asians, Latinx (allele frequencies ∼15{\%} to 23{\%}), and East Asians (∼38{\%}). The p.R208W allele was identified in ∼0.78{\%} of individuals overall with enrichment in Africans, Latinx, and East Asians (∼1.9–2.9{\%}). These and other novel Sigma1R variants provide tools for future studies to determine the molecular basis of Sigma1R association with emerin and the mechanism of nuclear lamina misregulation by cocaine and potentially other Sigma1R agonists. Impact statement: The Sigma-1 Receptor (Sigma1R; SIGMAR1) binds neuroactive drugs—both therapeutic and addictive—and associates with the nuclear membrane protein emerin and its partners lamin A/C and BANF1 in response to cocaine, through unknown mechanisms. We identified two novel SIGMAR1 missense variants of special interest due to their prevalence in human populations and their potential to perturb Sigma1R function at the nuclear envelope. Despite its importance in physiology and pharmacology, many aspects of Sigma1R including its membrane topology are unclear. Our findings lay the foundation for future molecular studies to understand how Sigma1R associates with emerin, lamin A/C, and BANF1 and manipulates their activity in response to agonist.",
keywords = "BANF1, cocaine, Emerin, LMNA, nuclear lamina, Sigma-1 receptor",
author = "Arun, {Adith S.} and Eddings, {Chelsy R.} and Wilson, {Katherine Lee}",
year = "2019",
month = "1",
day = "1",
doi = "10.1177/1535370219863444",
language = "English (US)",
journal = "Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N. Y.)",
issn = "0037-9727",
publisher = "Society for Experimental Biology and Medicine",

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TY - JOUR

T1 - Novel missense alleles of SIGMAR1 as tools to understand emerin-dependent gene silencing in response to cocaine

AU - Arun, Adith S.

AU - Eddings, Chelsy R.

AU - Wilson, Katherine Lee

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Sigma-1 receptor (Sigma1R; SIGMAR1), an integral membrane protein of the endoplasmic reticulum and nuclear envelope, has a hydrophobic drug-binding pocket that binds with high affinity to addictive drugs (cocaine, methamphetamine) and therapeutics used to treat a wide spectrum of neurological disorders. Cocaine enhances Sigma1R association with three nuclear lamina proteins (emerin, lamin A/C, BANF1), causing Sigma1R-dependent and emerin-dependent recruitment and transcriptional repression of a gene, MAOB1, involved in dopamine removal from neural synapses. The mechanism of Sigma1R association with emerin and the molecular impact of cocaine on their association are unknown. Mutations in Sigma1R, as a proposed regulator or mis-regulator of the nuclear lamina, have the potential to alter nuclear lamina function in brain or other tissues. We examined the frequency of SIGMAR1 missense alleles among 60,706 unrelated individuals in the ExAC database. We identified two novel SIGMAR1 missense variants of particular interest due to their frequency and potential to impact molecular association with emerin or other nuclear lamina proteins. Variant p.Q2P was widespread in ExAC (overall allele frequency 18.4%) with broad ethnic distribution among non-Finnish Europeans, Africans, South Asians, Latinx (allele frequencies ∼15% to 23%), and East Asians (∼38%). The p.R208W allele was identified in ∼0.78% of individuals overall with enrichment in Africans, Latinx, and East Asians (∼1.9–2.9%). These and other novel Sigma1R variants provide tools for future studies to determine the molecular basis of Sigma1R association with emerin and the mechanism of nuclear lamina misregulation by cocaine and potentially other Sigma1R agonists. Impact statement: The Sigma-1 Receptor (Sigma1R; SIGMAR1) binds neuroactive drugs—both therapeutic and addictive—and associates with the nuclear membrane protein emerin and its partners lamin A/C and BANF1 in response to cocaine, through unknown mechanisms. We identified two novel SIGMAR1 missense variants of special interest due to their prevalence in human populations and their potential to perturb Sigma1R function at the nuclear envelope. Despite its importance in physiology and pharmacology, many aspects of Sigma1R including its membrane topology are unclear. Our findings lay the foundation for future molecular studies to understand how Sigma1R associates with emerin, lamin A/C, and BANF1 and manipulates their activity in response to agonist.

AB - Sigma-1 receptor (Sigma1R; SIGMAR1), an integral membrane protein of the endoplasmic reticulum and nuclear envelope, has a hydrophobic drug-binding pocket that binds with high affinity to addictive drugs (cocaine, methamphetamine) and therapeutics used to treat a wide spectrum of neurological disorders. Cocaine enhances Sigma1R association with three nuclear lamina proteins (emerin, lamin A/C, BANF1), causing Sigma1R-dependent and emerin-dependent recruitment and transcriptional repression of a gene, MAOB1, involved in dopamine removal from neural synapses. The mechanism of Sigma1R association with emerin and the molecular impact of cocaine on their association are unknown. Mutations in Sigma1R, as a proposed regulator or mis-regulator of the nuclear lamina, have the potential to alter nuclear lamina function in brain or other tissues. We examined the frequency of SIGMAR1 missense alleles among 60,706 unrelated individuals in the ExAC database. We identified two novel SIGMAR1 missense variants of particular interest due to their frequency and potential to impact molecular association with emerin or other nuclear lamina proteins. Variant p.Q2P was widespread in ExAC (overall allele frequency 18.4%) with broad ethnic distribution among non-Finnish Europeans, Africans, South Asians, Latinx (allele frequencies ∼15% to 23%), and East Asians (∼38%). The p.R208W allele was identified in ∼0.78% of individuals overall with enrichment in Africans, Latinx, and East Asians (∼1.9–2.9%). These and other novel Sigma1R variants provide tools for future studies to determine the molecular basis of Sigma1R association with emerin and the mechanism of nuclear lamina misregulation by cocaine and potentially other Sigma1R agonists. Impact statement: The Sigma-1 Receptor (Sigma1R; SIGMAR1) binds neuroactive drugs—both therapeutic and addictive—and associates with the nuclear membrane protein emerin and its partners lamin A/C and BANF1 in response to cocaine, through unknown mechanisms. We identified two novel SIGMAR1 missense variants of special interest due to their prevalence in human populations and their potential to perturb Sigma1R function at the nuclear envelope. Despite its importance in physiology and pharmacology, many aspects of Sigma1R including its membrane topology are unclear. Our findings lay the foundation for future molecular studies to understand how Sigma1R associates with emerin, lamin A/C, and BANF1 and manipulates their activity in response to agonist.

KW - BANF1

KW - cocaine

KW - Emerin

KW - LMNA

KW - nuclear lamina

KW - Sigma-1 receptor

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