Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy

Hauger, Richard L.; Olivares-Reyes, J. Alberto; Dautzenberg, Frank M.; Lohr, James B.; Braun, Sandra; Oakley, Robert H.

doi:10.1016/j.neuropharm.2011.11.007

Cited by 71Posttraumatic Stress Disorder ResearchStress Responses and CortisolNeurotransmitter Receptor Influence on Behavior

Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy

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Hauger, Richard L., Olivares-Reyes, J. Alberto, Dautzenberg, Frank M., Lohr, James B., Braun, Sandra, Oakley, Robert H.·2012·Neuropharmacology

DOI 10.1016/j.neuropharm.2011.11.007PMC PMC3545643

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Abstract

The reasons for differences in vulnerability or resilience to the development of posttraumatic stress disorder (PTSD) are unclear. Here we review key genetic diatheses and molecular targets especially signaling pathways that mediate responses to trauma and severe stress and their potential contribution to the etiology of PTSD. Sensitization of glucocorticoid receptor (GR) signaling and dysregulation of GR modulators FKBP5, STAT5B, Bcl-2, and Bax have been implicated in PTSD pathophysiology. Furthermore, Akt, NFκB, MKP-1, and p11, which are G protein-coupled receptor (GPCR) pathway molecules, can promote or prevent sustained high anxiety and depressive-like behavior following severe stress. Agonist-induced activation of the corticotropin-releasing factor CRF1 receptor is crucial for survival in the context of serious danger or trauma, but persistent CRF1 receptor hypersignaling when a threatening or traumatic situation is no longer present is maladaptive. CRF1 receptor single nucleotide polymorphisms (SNPs) can confer susceptibility or resilience to childhood trauma while a SNP for the PAC1 receptor, another class B1 GPCR, has been linked genetically to PTSD. GRK3 phosphorylation of the CRF1 receptor protein and subsequent binding of βarrestin2 rapidly terminate Gs-coupled CRF1 receptor signaling by homologous desensitization. A deficient GRK-βarrestin2 mechanism would result in excessive CRF1 receptor signaling thereby contributing to PTSD and co-morbid posttraumatic depression. Clinical trials are needed to assess if small molecule CRF1 receptor antagonists are effective prophylactic agents when administered immediately after trauma. βarrestin2-biased agonists for CRF receptors and possibly other GPCRs implicated in PTSD, however, may prove to be novel pharmacotherapy with greater selectivity and therapeutic efficacy.

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To date, findings mainly implicate two key genes: the GC response element (GRE) and the CRH-releasing hormone receptor 1 (CRHR1) of the FKBP5 gene.
“To date, findings mainly implicate two key genes: the GC response element (GRE) and the CRH-releasing hormone receptor 1 (CRHR1) of the FKBP5 gene (383, 384).”
From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [384]
Section 2, “Potential Genes for PTSD Pathophysiology” (page not provided), links FKBP5 variants to PTSD risk and discusses the CRF1 receptor gene as a separate potential contributor. It does not identify a glucocorticoid response element (GRE) as one of two key genes or describe CRF1/CRHR1 as part of the FKBP5 gene. The claim conflates distinct biological entities. (LLM, conf=0.88)
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Institute of Medicine Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence 2008 The National Academies Press Washington DC

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Authors: Hauger, R. L., Olivares-Reyes, J. A., Dautzenberg, F. M., Lohr, J. B., Braun, S., & Oakley, R. H.
Affiliations: University of California San Diego (US)
Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (MX)
National Institutes of Health (US)
Corresponding author: Hauger, Richard L.
ORCID: Hauger, Richard L.
Olivares-Reyes, J. Alberto
Braun, Sandra
Oakley, Robert H.
Venue: Neuropharmacology
Publisher: Elsevier BV
Published: 2012-02
Volume: 62
Issue: 2
Pages: 705-714
ISSN: 0028-3908 (ISSN-L)
DOI: 10.1016/j.neuropharm.2011.11.007
PMC: PMC3545643
OpenAlex: W2147525819
Semantic Scholar: bfcd909ff6036d3502e4b2063ab4d7a587ac7d62
Cited by: 71
References: 85
Citations by year: 2024: 2 · 2023: 12 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 9 · 2014: 6 · 2013: 9 · 2012: 3
FWCI: 0.88
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuropharmacology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute on Aging (R01AG018386, AG018386)
National Institute of Mental Health (MH074697, R01MH074697)
Topics: Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: post-traumatic stress disorder, glucocorticoid receptor signaling, FKBP5, STAT5B, Bcl-2, Bax, Akt, NF-κB, MKP-1, p11, G protein-coupled receptors, corticotropin-releasing factor 1 receptor, PAC1 receptor, GRK3, β-arrestin2, receptor desensitization, single nucleotide polymorphisms, childhood trauma, post-traumatic depression, PTSD pharmacotherapy, stress resilience, anxiety-like behavior, depression-like behavior
MeSH terms: Humans, Phosphorylation, Receptors, Glucocorticoid, Stress Disorders, Post-Traumatic, Signal Transduction, Receptors, Corticotropin-Releasing Hormone

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