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'.