Characterization Of Lymphocyte β₂‐Adrenoceptor Signalling In Patients With Left Ventricular Volume Overload Disease

Abstract

1. Studies using animal experimental models have suggested that the beta2-adrenoceptor is uncoupled in association with alterations in the expression of G-protein-coupled receptor kinases (GRK) 2/3 in heart failure. However, the functional expression of the components of this pathway in human disease has not been fully elucidated yet. In the present study, we evaluated the possibility that the regulation of beta2-adrenoceptor signalling components in patients with left ventricular volume overload (VOL) depends on the severity of the overload. 2. We characterized the lymphocyte GRK 2-6, beta-arrestins 1 and 2, beta2-adrenoceptor expression at the mRNA and protein levels, as well as the activity of adenylyl cyclase, protein kinases (PK) A and PKC in patients with VOL using healthy blood donors as controls. 3. In the patient group, GRK2 mRNA was increased by 61% (P < 0.001), GRK3 was increased by 54% (P < 0.005), GRK5 was increased fivefold (P < 0.001) and the beta-arrestin 2 mRNA was increased by 40% (P < 0.05). These increases were paralleled with a sixfold increase in GRK2, a twofold increase in GRK3 and a 1.3-fold increase in GRK5 protein levels. These changes were associated with a significant decrease in beta2-adrenoceptor mRNA, the basal, catalytic and receptor-mediated activity of adenylyl cyclase and sensitization of the forskolin-stimulated activity towards augmented inhibition by guanylimidodiphosphate. In general, the increase in GRK2 and 5 mRNA exhibited a positive correlation with the gravity of the haemodynamic load, as determined by changes in left ventricular fractional shortening. 4. The results suggest that VOL induces an increase in the expression of lymphocyte beta2-adrenoceptor-specific GRK and beta-arrestin 2 in association with an attenuation in beta2-adrenoceptor levels. It can be speculated that the cardiac circulatory system adapts itself to altered haemodynamic functional demands partly by altering beta2-adrenoceptor signalling.

GRK5-Mediated Exacerbation of Pathological Cardiac Hypertrophy Involves Facilitation of Nuclear NFAT Activity

“…G protein-coupled receptor (GPCR) kinases (GRKs) phosphorylate these receptors leading to their desensitization and down-regulation 3 . GRK2 and GRK5, the two major GRKs in the heart, are in fact up-regulated in HF leading to a loss of the heart’s inotropic reserve 4-6 . In fact, GRK2 inhibition and the improved resensitization of β-AR signaling in the failing heart has led to HF reversal and a potential therapeutic strategy 7 .…”

A GRK5 polymorphism that inhibits β-adrenergic receptor signaling is protective in heart failure

“…Of particular interest is the rapid up-and down-regulation of GRK2 that correlates with ventricular function 17,18 , which implies that the role of this GRK in the heart may be acute regulation. On the other hand, GRK5 expression appears to less dynamic and may therefore be more important in chronic regulation 19,20 . As such, GRK5-mediated βAR desensitization could provide adaptive, beneficial effects during early ventricular decompensation, and prior to frank failure.…”

Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure ethiology and correlates to clinical variables

“…Differences among the GRKs in subcellular localization, activation mechanism, and receptor specificity suggest that they may play nonredundant modulatory roles in the heart (9,10,14,15,24). The rapid up-and downregulation of GRK2 and the less dynamic changes in the GRK5 expression are of particular interest, suggesting that GRK2 may function predominantly in the acute modulation of ␤-AR signaling, whereas GRK5 may prove more important for chronic modulation (20).…”