11-cis-retinal and Hypertension

G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptors (GPCRs) to effect receptor phosphorylation and to initiate profound impairment of receptor signalling, or desensitization. GPCRs form the largest family of cell surface receptors known and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations. This review focuses on the physiological role of GRKs revealed by genetically modified animals but also develops the involvement of GRKs in human diseases as, Oguchi disease, heart failure, hypertension or rhumatoid arthritis. Furthermore, the regulation of GRK levels in opiate addiction, cancers, psychiatric diseases, cystic fibrosis and cardiac diseases is discussed. Both transgenic mice and human pathologies have demonstrated the importance of GRKs in the signalling pathways of rhodopsin, beta-adrenergic and dopamine-1 receptors. The modulation of GRK activity in animal models of cardiac diseases can be effective to restore cardiac function in heart failure and opens a novel therapeutic strategy in diseases with GPCR dysregulation.

Topics: Animals; Arthritis, Rheumatoid; Cell Membrane; Cyclic AMP-Dependent Protein Kinases; Heart Diseases; Humans; Hypertension; Mice; Mice, Transgenic; Models, Biological; Neoplasms; Phosphorylation; Protein Kinases; Receptors, Adrenergic, beta; Receptors, Dopamine; Receptors, G-Protein-Coupled; Rhodopsin; Signal Transduction

The citric acid cycle is central to the regulation of energy homeostasis and cell metabolism. Mutations in enzymes that catalyse steps in the citric acid cycle result in human diseases with various clinical presentations. The intermediates of the citric acid cycle are present at micromolar concentration in blood and are regulated by respiration, metabolism and renal reabsorption/extrusion. Here we show that GPR91 (ref. 3), a previously orphan G-protein-coupled receptor (GPCR), functions as a receptor for the citric acid cycle intermediate succinate. We also report that GPR99 (ref. 4), a close relative of GPR91, responds to alpha-ketoglutarate, another intermediate in the citric acid cycle. Thus by acting as ligands for GPCRs, succinate and alpha-ketoglutarate are found to have unexpected signalling functions beyond their traditional roles. Furthermore, we show that succinate increases blood pressure in animals. The succinate-induced hypertensive effect involves the renin-angiotensin system and is abolished in GPR91-deficient mice. Our results indicate a possible role for GPR91 in renovascular hypertension, a disease closely linked to atherosclerosis, diabetes and renal failure.

Topics: Animals; Antihypertensive Agents; Captopril; Cattle; Cell Line; Citric Acid Cycle; Cricetinae; Humans; Hypertension; Ketoglutaric Acids; Kidney; Ligands; Mice; Models, Molecular; Pertussis Toxin; Protein Conformation; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Rhodopsin; RNA, Messenger; Succinic Acid; Swine

Impaired vascular beta-adrenergic responsiveness may play an important role in the development and/or maintenance of hypertension. This defect has been associated with an alteration in receptor/guanine nucleotide regulatory protein (G-protein) interactions. However, the locus of this defect remains unclear. G-Protein-coupled receptor kinases (GRKs) phosphorylate serine/threonine residues on G-protein-linked receptors in an agonist-dependent manner. GRK activation mediates reduced receptor responsiveness and impaired receptor/G-protein coupling. To determine whether the impairment in beta-adrenergic response in human hypertension might be associated with altered GRK activity, we studied lymphocytes from younger hypertensive subjects as compared with older and younger normotensive subjects. We assessed GRK activity by rhodopsin phosphorylation and GRK expression by immunoblot. GRK activity was significantly increased in lymphocytes from younger hypertensive subjects and paralleled an increase in GRK-2 (beta ARK-1) protein expression. In contrast, no alterations in cAMP-dependent kinase (A-kinase) activity or GRK-5/6 expression were noted. GRK activity was not increased in lymphocytes from older normotensive subjects who demonstrated a similar impairment in beta-adrenergic-mediated adenylyl cyclase activation. These studies indicate that GRK activity is selectively increased in lymphocytes from hypertensive subjects. The increase in GRK activity may underlie the reduction in beta-adrenergic responsiveness characteristic of the hypertensive state.

Topics: Adenylyl Cyclases; Adult; Aged; Aging; Arrestin; beta-Adrenergic Receptor Kinases; Cell Membrane; Cyclic AMP-Dependent Protein Kinases; G-Protein-Coupled Receptor Kinase 5; G-Protein-Coupled Receptor Kinases; Humans; Hypertension; Immunoblotting; Lymphocytes; Male; Middle Aged; Phosphorylation; Protein Serine-Threonine Kinases; Receptor Protein-Tyrosine Kinases; Receptors, Adrenergic, beta; Rhodopsin

To determine whether chronic systemic hypertension alters the response of photoreceptors to photic stress.. Spontaneously hypertensive rats and strain-matched, normotensive Wistar-Kyoto rats were exposed to green fluorescent light (490 to 580 nm, 180 to 200 foot-candles) for 24 hours. Retinal changes were evaluated by histopathologic examination, morphometry of the outer nuclear layer, and rhodopsin levels.. Before light exposure, spontaneously hypertensive rats developed elevated systolic blood pressure and showed mild sclerosis of choroidal vasculature. After exposure, retinas of the spontaneously hypertensive rats revealed exaggerated light damage with increased loss of photoreceptor cells, more distortion, and shortening of the inner and outer segments relative to the normotensive Wistar-Kyoto rats. The outer nuclear layer thickness and rhodopsin level were significantly lower in spontaneously hypertensive rats than in the normotensive Wistar-Kyoto rats by day 14 after light exposure.. Photic injury to photoreceptor cells was exaggerated in spontaneously hypertensive rats. This may have clinical relevance given the association of both systemic hypertension and light exposure in patients with age-related macular degeneration.

Topics: Animals; Blood Pressure; Chronic Disease; Hypertension; Light; Male; Photoreceptor Cells; Radiation Injuries, Experimental; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Retina; Rhodopsin; Stress, Physiological