The role of G protein coupled receptor kinases in neurocardiovascular pathophysiology

Abstract

In coronary artery disease the G protein related kinases (GRKs) play a role in desensitization of β-adrenoreceptors (AR) after coronary occlusion. Targeted deletion and lowering of cardiac myocyte GRK-2 decreases the risk of post-ischemic heart failure (HF). Studies carried out in humans confirm the role of GRK-2 as a marker for the progression of HF after myocardial infarction (MI). The level of GRK-2 could be an indicator of β-AR blocker efficacy in patients with acute coronary syndrome. Elevated levels of GRK-2 are an early ubiquitous consequence of myocardial injury. In hypertension an increased level of GRK-2 was reported in both animal models and human studies. The role of GRKs in vagally mediated disorders such as vasovagal syncope and atrial fibrillation remains controversial. The role of GRKs in the pathogenesis of neurocardiological diseases provides an insight into the molecular pathogenesis process, opens potential therapeutic options and suggests new directins for scientific research.

Keywords: autonomic; molecular signaling pathway; sympathetic; vagal.

Figure 1

A schematic representation of events after agonist binding to β-AR. A – Agonist binding to β-AR and AC activation via G protein signaling, leading to PKA activation and GRK-2 mediated β-AR phosphorylation causing receptor desensitization. B – Subsequent recruitment of β-arrestin to the receptor and interactions with the signaling protein PDE4 resulting in the attenuation of receptor desensitization and internalization β-AR – β-adrenoceptor, Gs – stimulatory G protein α subunit, G_βγ – G protein βγ subunit, AC – adenylate cyclase, ATP – adenosine triphosphate, ADP – adenosine diphosphate, AMP – adenosine monophosphate, cAMP – cyclic adenosine monophosphate, PKA – cAMP dependent kinase, GRK-2 – GPCR kinase 2, PDE4 – phosphodiesterase-4