Differential effects of inescapable stress on locus coeruleus GRK3, alpha2-adrenoceptor and CRF1 receptor levels in learned helpless and non-helpless rats: A potential link to stress resilience

Abstract

Exposure of rats to unpredictable, inescapable stress results in two distinct behaviors during subsequent escape testing. One behavior, suggestive of lack of stress resilience, is prolonged escape latency compared to non-stressed rats and is labeled learned helplessness (LH). The other behavior suggestive of stress resilience is normal escape latency and is labeled non-helpless (NH). This study examines the effects of unpredictable, inescapable tail-shock stress (TSS) on alpha2-adrenoceptor (α2-AR) and corticotropin-releasing factor 1 receptor (CRF1) regulation as well as protein levels of G protein-coupled receptor kinase 3 (GRK3), GRK2, tyrosine hydroxylase (TH) plus carbonylated protein levels in locus coeruleus (LC), amygdala (AMG), cortex (COR) and striatum (STR). In NH rats, α2-AR and CRF1 receptors were significantly down-regulated in LC after TSS. No changes in these receptor levels were observed in the LC of LH rats. GRK3, which phosphorylates receptors and thereby contributes to α2-AR and CRF1 receptor down-regulation, was reduced in the LC of LH but not NH rats. GRK2 levels were unchanged. In AMG, GRK3 but not GRK2 levels were reduced in LH but not NH rats, and receptor regulation was impaired in LH rats. In STR, no changes in GRK3 or GRK2 levels were observed. Finally, protein carbonylation, an index of oxidative stress, was increased in the LC and AMG of LH but not NH rats. We suggest that reduced stress resilience after TSS may be related to oxidative stress, depletion of GRK3 and impaired regulation of α2-AR and CRF1 receptor in LC.

Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy

“…Current evidence indicates that a large deficiency in GRK3 results in CRF 1 receptor supersensitivity, while high cellular levels of GRK3 maximize CRF 1 receptor desensitization (Dautzenberg et al 2001; Figures 2-3). Interestingly, GRK3 protein levels in the amygdala and locus coeruleus are significantly reduced in rats developing learned helplessness after unpredictable, inescapable stress, while resilience to this severe stressor is associated with normal GRK3 expression and function (Taneja et al 2011). CRF-induced activation of CRF 1 receptors promotes one of the strongest translocation responses of βarrestin2 from cytosol to cell surface observed for studied class A GPCRs (Hauger et al 2009).…”

G protein-coupled receptor kinases: More than just kinases and not only for GPCRs

“…Administration of GPCR antagonists or removal of endogenous agonists also can affect the GRK concentration (Hurle, 2001; Diaz et al, 2002; Bezard et al, 2005; Ahmed et al, 2007; Ahmed et al, 2008; Ahmed et al, 2010). The concentration of GRKs in vivo and in cultured cells is responsive to various conditions such as stress (Taneja et al, 2011), neonatal ventral hippocampal lesion (Bychkov et al, 2010), cell cycle progression (Penela et al, 2010), and drug treatment (Salim et al, 2007). Human diseases alter GRK levels.…”

“…The role of GRK3 is likely to facilitate the recruitment of arrestins to κ-opioid receptors, since κ-opioid receptor-induced p38 activation is GRK3- and arrestin-dependent (Bruchas et al, 2006). Learned helplessness, a behavior considered an animal model of depression (Vollmayr and Henn, 2001), is associated with reduced GRK3 expression in the locus coeruleus and amygdala in rats, whereas rats that do not develop learned helplessness following forced swim have normal GRK3 expression (Taneja et al, 2011). This deficit in the GRK3 expression seems linked to the dysregulation of the α2-adrenoreceptors and corticotropin releasing factor 1 receptors in rats with learned helplessness.…”

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

“…GRK2 primarily targets several GPCRs including ␤-ARs and angiotensin II type 1 receptors, and it is expressed in most tissues. GRK3 targets olfactory receptors, thrombin receptors, kappa-opioid CRF1 (57,219), and ␣1-and ␣2-ARs (12,246). It is found in most tissues, but most prominently in the olfactory epithelium.…”