Protein Profiling of RGS6, a Pleiotropic Gene Implicated in Numerous Neuropsychiatric Disorders, Reveals Multi-Isoformic Expression and a Novel Brain-Specific Isoform

K E Ahlers-Dannen; J Yang; M M Spicer; B Maity; A Stewart; J G Koland; R A Fisher

doi:10.1523/ENEURO.0379-21.2021

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Protein Profiling of RGS6, a Pleiotropic Gene Implicated in Numerous Neuropsychiatric Disorders, Reveals Multi-Isoformic Expression and a Novel Brain-Specific Isoform

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Protein Profiling of RGS6, a Pleiotropic Gene Implicated in Numerous Neuropsychiatric Disorders, Reveals Multi-Isoformic Expression and a Novel Brain-Specific Isoform

K E Ahlers-Dannen, J Yang, M M Spicer, B Maity, A Stewart, J G Koland and R A Fisher

eNeuro, Vol.9(1), p.ENEURO.0379-21.2021

01/2022

DOI: 10.1523/ENEURO.0379-21.2021

PMCID: PMC8805202

PMID: 34880111

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Abstract

A metanalysis identified regulator of G-protein signaling 6 ( ) as one of 23 loci with pleiotropic effects on four or more human psychiatric disorders. This finding is significant as it confirms/extends the findings of numerous other studies implicating RGS6 in CNS function and pathology. RGS6 is a highly conserved member of the RGS protein family whose cellular roles are likely affected by mRNA splicing and alternative domain inclusion/exclusion. Indeed, we previously identified multiple RGS6 splice variants predicted to produce 36 distinct protein isoforms containing either long (RGS6L) or short (RGS6S) N-terminal domains, an incomplete or intact GGL domain, and nine alternative C termini. Unfortunately, sequence similarities between the isoforms have made it difficult to confirm their individual existence and/or to determine their unique functions. Here, we developed three RGS6-specific antibodies that recognize all RGS6 protein isoforms (RGS6-fl), the N-terminus of RGS6L isoforms (RGS6-L), and an 18-amino acid alternate C-terminal sequence (RGS6-18). Using these antibodies, we demonstrate that RGS6L(+GGL) isoforms, predominating in both mouse (both sexes) CNS and peripheral tissues, are most highly expressed in the CNS. We further identify three novel RGS6 protein bands that are larger (61, 65, and 69-kDa) than the ubiquitously expressed 53- to 57-kDa RGS6L(+GGL) proteins. Importantly, we show that the 69-kDa protein is a brain-specific dephospho form of the 65-kDa band, the first identified phosphorylated RGS6 isoform. Together, these data begin to define the functional significance behind the complexity of gene processing and further clarifies RGS6's physiological roles by resolving tissue-specific RGS6 protein expression.

Animals

Brain - metabolism

Genetic Pleiotropy

GTP-Binding Proteins - metabolism

Mice

Protein Isoforms - genetics

RGS Proteins - genetics

Details

Title: Subtitle: Protein Profiling of RGS6, a Pleiotropic Gene Implicated in Numerous Neuropsychiatric Disorders, Reveals Multi-Isoformic Expression and a Novel Brain-Specific Isoform
Creators: K E Ahlers-Dannen - University of Iowa
J Yang - University of Iowa
M M Spicer - Roy J. and Lucille A. Carver College of Medicine
B Maity - Roy J. and Lucille A. Carver College of Medicine
A Stewart - Roy J. and Lucille A. Carver College of Medicine
J G Koland - University of Iowa
R A Fisher - Roy J. and Lucille A. Carver College of Medicine
Resource Type: Journal article
Publication Details: eNeuro, Vol.9(1), p.ENEURO.0379-21.2021
DOI: 10.1523/ENEURO.0379-21.2021
PMID: 34880111
PMCID: PMC8805202
NLM abbreviation: eNeuro
ISSN: 2373-2822
eISSN: 2373-2822
Grant note: R01 AA025919 / NIAAA NIH HHS R01 CA161882 / NCI NIH HHS
Language: English
Date published: 01/2022
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984303852102771

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