title: Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy.
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 CRF(1) receptor is crucial for survival in the context of serious danger or trauma, but persistent CRF(1) receptor hypersignaling when a threatening or traumatic situation is no longer present is maladaptive. CRF(1) 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 CRF(1) receptor protein and subsequent binding of βarrestin2 rapidly terminate Gs-coupled CRF(1) receptor signaling by homologous desensitization. A deficient GRK-βarrestin2 mechanism would result in excessive CRF(1) receptor signaling thereby contributing to PTSD and co-morbid posttraumatic depression. Clinical trials are needed to assess if small molecule CRF(1) 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. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
authors: Center of Excellence for Stress and Mental Health, VA Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. rhauger@ucsd.edu
authors: Richard L
authors: RL
authors: Hauger
authors: J Alberto
authors: JA
authors: Olivares-Reyes
authors: Frank M
authors: FM
authors: Dautzenberg
authors: James B
authors: JB
authors: Lohr
authors: Sandra
authors: S
authors: Braun
authors: Robert H
authors: RH
authors: Oakley
mesh_terms: D006801:Humans; D010766:Phosphorylation; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013313:Stress Disorders, Post-Traumatic / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid