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Second Messengers, Trafficking-Related Proteins, and Amino Acid Residues that Contribute to the Functional Regulation of the Rat Brain GABA Transporter GAT1

Quick, Michael W. and Corey, Janis L. and Davidson, Norman and Lester, Henry A. (1997) Second Messengers, Trafficking-Related Proteins, and Amino Acid Residues that Contribute to the Functional Regulation of the Rat Brain GABA Transporter GAT1. Journal of Neuroscience, 17 (9). pp. 2967-2979. ISSN 0270-6474. PMCID PMC6573650. https://resolver.caltech.edu/CaltechAUTHORS:20191030-140944005

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Abstract

Recent evidence indicates that several members of the Na⁺-coupled transporter family are regulated, and this regulation in part occurs by redistribution of transporters between intracellular locations and the plasma membrane. We elucidate components of this process for both wild-type and mutant GABA transporters (GAT1) expressed in Xenopus oocytes using a combination of uptake assays, immunoblots, and electrophysiological measurements of membrane capacitance, transport-associated currents, and GAT1-specific charge movements. At low GAT1 expression levels, activators of protein kinase C (PKC) induce redistribution of GAT1 from intracellular vesicles to the plasma membrane; at higher GAT1 expression levels, activators of PKC fail to induce this redistribution. However, coinjection of total rat brain mRNA with GAT1 permits PKC-mediated modulation at high transporter expression levels. This effect of brain mRNA on modulation is mimicked by coinjection of syntaxin 1a mRNA and is eliminated by injecting synaptophysin or syntaxin antisense oligonucleotides. Additionally, botulinum toxins, which inactivate proteins involved in vesicle release and recycling, reduce basal GAT1 expression and prevent PKC-induced translocation. Mutant GAT1 proteins, in which most or all of a leucine heptad repeat sequence was removed, display altered basal distribution and lack susceptibility to modulation by PKC, delineating one region of GAT1 necessary for its targeting. Thus, functional regulation of GAT1 in oocytes occurs via components common to transporters and to trafficking in both neural and non-neural cells, and suggests a relationship between factors that control neurotransmitter secretion and the components necessary for neurotransmitter uptake.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1523/jneurosci.17-09-02967.1997DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573650PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 1997 Society for Neuroscience. Received Aug. 9, 1996; revised Jan. 23, 1997; accepted Feb. 13, 1997. This research was supported by United States Public Health Service Grants NS-11756 (H.A.L.), DA-09121 (H.A.L.), DA-10509 (M.W.Q.), National Research Service Award fellowships (M.W.Q. and J.L.C.), and the W. M. Keck Foundation 931360 (M.W.Q).
Funders:
Funding AgencyGrant Number
NIHNS-11756
NIHDA-09121
NIHDA-10509
NIH Predoctoral FellowshipUNSPECIFIED
W. M. Keck Foundation931360
Subject Keywords:neurotransmitter transporters; intracellular trafficking; leucine heptad repeats; synaptic vesicle proteins; second messengers; protein regulation
Issue or Number:9
PubMed Central ID:PMC6573650
Record Number:CaltechAUTHORS:20191030-140944005
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20191030-140944005
Official Citation:Second Messengers, Trafficking-Related Proteins, and Amino Acid Residues that Contribute to the Functional Regulation of the Rat Brain GABA Transporter GAT1. Michael W. Quick, Janis L. Corey, Norman Davidson, Henry A. Lester. Journal of Neuroscience 1 May 1997, 17 (9) 2967-2979; DOI: 10.1523/JNEUROSCI.17-09-02967.1997
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99563
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Oct 2019 21:46
Last Modified:30 Oct 2019 21:46

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