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Psychiatric Drugs Bind to Classical Targets Within Early Exocytotic Pathways: Therapeutic Effects

Lester, Henry A. and Miwa, Julie M. and Srinivasan, Rahul (2012) Psychiatric Drugs Bind to Classical Targets Within Early Exocytotic Pathways: Therapeutic Effects. Biological Psychiatry, 72 (11). pp. 907-915. ISSN 0006-3223. PMCID PMC6167061. doi:10.1016/j.biopsych.2012.05.020. https://resolver.caltech.edu/CaltechAUTHORS:20121217-074942263

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Abstract

The classical targets for antipsychotic and antidepressant drugs are G protein-coupled receptors and neurotransmitter transporters, respectively. Full therapeutic actions of these drugs require several weeks. We show how therapeutic effects may eventually accrue after existing therapeutic ligands bind to these classical targets, not on the plasma membrane but rather within endoplasmic reticulum (ER) and cis-Golgi. Consequences of such binding may include pharmacological chaperoning: the nascent drug targets are stabilized against degradation and can therefore exit the ER more readily. Another effect may be matchmaking: heterodimers and homodimers of the target form and can more readily exit the ER. Summarizing recent data for nicotinic receptors, we explain how such effects could lead to reduced ER stress and to a decreased unfolded protein response, including changes in gene activation and protein synthesis. In effects not directly related to cellular stress, escorting would allow increased ER exit and trafficking of known associated proteins, as well as other proteins such as growth factors and their receptors, producing both cell-autonomous and non-cell-autonomous effects. Axonal transport of relevant proteins may underlie the several weeks required for full therapy. In contrast, the antidepressant effects of ketamine and other N-methyl-D-aspartate receptor ligands, which occur within <2 hours, could arise from dendritically localized intracellular binding, followed by chaperoning, matchmaking, escorting, and reduced ER stress. Thus, the effects of intracellular binding extend beyond proteostasis of the targets themselves and involve pathways distinct from ion channel and G protein activation. We propose experimental tests and note pathophysiological correlates.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.biopsych.2012.05.020DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167061/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2012 Society of Biological Psychiatry. Received Mar 21, 2012; revised Apr 23, 2012; accepted May 21, 2012. This work was supported by the National Institutes of Health (MH-086383 and MH-088550). Our laboratory’s work on nicotinic receptors has been supported by the National Institutes of Health (AG-33954, DA-17279, DA-19375), the Michael J. Fox Foundation, the Joint Center for Translational Medicine, the California Tobacco-Related Disease Research Program (17RT-0127, 18FT-0066, 19KT-0032), and Targacept, Inc. In the past, our laboratory’s work on G protein-coupled receptors has been supported by GM-081662, on neurotransmitter transporters by DA-09121, and on intracellular messengers by GM-29836. HAL, JMM, and RS wrote the article. HAL developed the concepts. JMM contributed ideas on lynx. RS contributed scholarship on the unfolded protein response. We thank Hadassah Tamir for suggesting that axonal transport underlies some aspects of psychiatric drug effects and for discussion, Johannes Schwarz for pointing out aspects of dyskinesia, and Luke Wiseman for tutorials on the unfolded protein response.Wealso thank Nathan Dascal, Dennis Dougherty, Hesso Farhan, Robert Farley, Robert Freedman, Ege Kavalali, Odile Kellermann, Jun Li,JohnLowe, Stefan McDonough, J. Michael McIntosh, Randy Schekman, Darryle Schoepp, Andrew Steele, Teagan Wall, and the anonymous referees for comments. HAL thanks members of our research group for discussion and for allowing the time to assemble this essay. HAL has submitted patent applications covering pharmacological chaperones in neurodegenerative and psychiatric disease. JMM is founder and shareholder of Ophidion, Inc. She has applied for US patents 10322359 and 20080221013 on the use of lynx for therapeutic purposes. RS reports no biomedical financial interests or potential conflicts of interest.
Funders:
Funding AgencyGrant Number
NIHMH-86383
NIHMH-088550
NIHAG-33954
NIHDA-17279
NIHDA-19375
Michael J. Fox FoundationUNSPECIFIED
Joint Center for Translational MedicineUNSPECIFIED
California Tobacco-Related Disease Research Program17RT-0127
California Tobacco-Related Disease Research Program18FT-0066
California Tobacco-Related Disease Research Program19KT-0032
Targacept, Inc.UNSPECIFIED
NIHGM-081662
NIHDA-09121
NIHGM-29836
Subject Keywords:Antipsychotics; depression; gene activation; nicotine; schizophrenia; serotonin selective reuptake inhibitors
Issue or Number:11
PubMed Central ID:PMC6167061
DOI:10.1016/j.biopsych.2012.05.020
Record Number:CaltechAUTHORS:20121217-074942263
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20121217-074942263
Official Citation:Henry A. Lester, Julie M. Miwa, Rahul Srinivasan, Psychiatric Drugs Bind to Classical Targets Within Early Exocytotic Pathways: Therapeutic Effects, Biological Psychiatry, Volume 72, Issue 11, 1 December 2012, Pages 907-915, ISSN 0006-3223, 10.1016/j.biopsych.2012.05.020. (http://www.sciencedirect.com/science/article/pii/S0006322312004891)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35998
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:17 Dec 2012 16:24
Last Modified:09 Nov 2021 23:19

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