Lokalizace a funkce adrenergních receptorů beta 3

Adipose tissue

• 1984 the beta 3 receptor was described as the third group of beta receptors in adipose tissue [1]
• This lead to the development of agonist targeted at obesity and diabetes [1]
• In adipocytes, where it mediates the adrenergic ß-oxidation of fatty acids

Myokard

• Beta3-adrenergic receptors - cardiodepressant effects in human ventricles
• Did not fit to its stimulatory properties of adenylyl cyclase in other tissues
• Great importance in pathological conditions and remains undetermined [3]
• Immunodetection of proteins in human atrial and ventricular cardiac myocytes
• Endothelial cells of the small coronary resistance vessels
• B3AR expression is increased in human cardiac tissue from heart failure patients
• In whom B1-2 AR are known to be decreased and desensitized [12]
• Up-regulation of cardiac B3AR in diabetic hearts in several animal models [12]
• In some vessels, B3AR are expressed in both vascular smooth muscle cells and endothelial cells, or in endothelium only
• B3AR activation generally produces vasorelaxation
• May depend on the pre-constricting agent used [12]
• Coupling of B3AR to intracellular effectors also varies according to the cell type
• Canine pulmonary arteries
• B3AR vasodilating effect is independent from the endothelium
• But coupled to an increase in cAMP levels [12]
• Activation of B3AR in endothelial cells
• Produces an endothelium-dependent relaxation in aortic and resistance vessels from many animal species
• NOS-dependent and -independent mechanisms [12]
• Bovine aortic endothelial cells
• B3AR promoted eNOS activation through phosphorylation on Ser1179
• De-phosphorylation on the inhibitory phosphoresidues Ser116 and Thr497
• B3AR signalling to eNOS was dependent on the enzyme's association to Rac1
• Which also induced endothelial cell migration in vitro [12]
• In human coronary resistance vessels
• B3AR-induced relaxation is mediated by both NO- and EDHF-dependent responses
• One proposed mediator is extracellular K+ that would drive hyperpolarization through activation of the Na+-K+-ATPase
• B3AR protects the beta1 subunit of NaKATPase from inactivation by oxidative S-glutathionylation
• Maintaining the pump activity in the face of oxidant stress, as occurring, e.g. in diabetes [12]
• In line with antioxidant effects of B3AR in a setting of acute ischaemia
• Contribute to maintain both NO and EDHF vasodilatory responses in disease
• Important paracrine protective signalling (e.g. through NO) to the underlying parenchymal cardiac tissue [12]
• In some vessel beds, B3AR also couple to Adenylyl Cyclase (AC)/cyclic AMP (cAMP)/protein kinase A (PKA)
• Directly relax vessels
• NO-induced pro-angiogenic effects in endothelial cells
• Vasorelaxing effects contribute to improved myocardial perfusion [12]
• B3AR decrease kardiomyocyte hypertrophy
• Antioxidant effects in CM and neighbouring cells such as fibroblasts (fib)
• Prevents hypertrophic and fibrotic remodelling
• Thereby preserving diastolic filling [12]
• Kardiomyocyte expression of the receptor varies from species to species
• Low expression in mice
• Higher in rats, rabbits, or dogs [12]
• Expression increases with disease
• In human ventricular biopsies, the B3AR-induced production of NO
• Sensitive to pertussis toxin
• Suggesting B3AR coupling to G-alpha-i proteins
• Coupled to NOS-dependent production of cGMP
• Transgenic mouse model expressing the human B3AR specifically in cardiac myocytes
• Receptor co-localized with caveolin3 and eNOS and nNOS in caveolae-enriched membrane fractions
• In rat neonatal cardiac myocytes
• B3AR activates nNOS through phosphorylation on Ser1412 and de-phosphorylation of Ser847
• As in human biopsies
• B3AR-induced post-translational modifications were also sensitive to G-alpha-i/o inhibition
• Whether B3AR can couple to G-alpha-s (and Adenylyl Cyclase/cAMP) in addition to G-alpha-i (as does B2AR in some conditions) is still unresolved
• Titin or troponin-I (TnI) phosphorylation would result in decreased myofilament calcium sensitivity
• Improved diastolic relaxation that would promote LV filling [12]
• Ica-L is increased by B3AR agonists in human atrial cells ex vivo
• Response is less prominent in ventricular cells
• Caution should be used in extrapolating data using high concentration of agonists in vitro with imperfect selectivity (and potential off-target effects on B1-2 ARs) [12]
• Property of B3AR is to oppose the classical positive inotropic effect of B1-2AR, thereby acting as a countervailing ‘brake’ to prevent adrenergic overactivation [12]
• B3AR may also regulate cardiac muscle relaxation
• Possibly through cGMP/PKG-dependent phosphorylation from NO within cardiac myocytes or paracrinally released from cardiac endothelium [12]
• Sheep study concluded
• Small negative inotropic effect in healthy sheep
• Improvement of inotropic parameters in sheep with heart failure
• Preservation of Na+-K+-ATPase function in failing cardiac myocytes
• Decrease intracellular Na+ content
• Reductions in Na+ content and late Na+ current proposed to improve relaxation
• Helpful in heart failure with preserved ejection fraction (HFpEF) [12]
• B3AR are also expressed in the pulmonary arterial vasculature in some species
• Contribute to attenuate pulmonary vasoconstriction
• Reduce pre-capillary pulmonary hypertension [12]
• Observed inhibition of fibroblasts activation upon B3AR expression in cardiac myocytes [12]
• In mice submitted to transaortic constriction (TAC)
• Decreased hypertrophy and preserved LV function [12]
• B3AR coupling to eNOS and nNOS in the beneficial effects of exercise on the heart
• Myocardial protection in the setting of ischaemia/reperfusion in mice
• Large (porcine) animal model
• Pre-perfusion of the B3AR agonist, BRL37344 reduced reperfusion damage and improved long-term LV function
• Akt/NO-mediated prevention of mitochondrial permeability transition pore (mPTP) opening

Small intestine

• Gastrointestinal tract [PMID: 7621895], where they regulates
• Lipolysis, thermogenesis and gut motility [PMID: 16457637, PMID: 15935402, PMID: 9808702] [10]

Vascular endothelium

• B3AR are also expressed in the pulmonary arterial vasculature in some species
• Contribute to attenuate pulmonary vasoconstriction
• Reduce pre-capillary pulmonary hypertension [12]
• Cévy myokardu [12]

Pokles tonu svaloviny m. měchýře

Ledviny

• Beta3 adrenergic receptor in the kidney may be a new player in sympathetic regulation of renal function.
• Expression and the possible physiologic role of beta3-adrenergic receptor (beta3-AR) in mouse kidney
• Antidiuretic effect of beta3-AR stimulation in the kidney
• Beta3-AR agonism might be useful to bypass AVPR2-inactivating mutations [7]

Beta3-AR is expressed in most of the nephron segments

• That also express the type 2 vasopressin receptor (AVPR2)
• Including the thick ascending limb
• The cortical and outer medullary collecting duct [7]

Ex vivo experiments in mouse kidney tubules

• Beta3-AR stimulation with the selective agonist BRL37344
• Increased intracellular cAMP levels
• Promoted 2 key processes in the urine concentrating mechanism
• Accumulation of the water channel aquaporin 2 at the apical plasma membrane in the collecting duct
• Activation of the Na-K-2Cl symporter in the thick ascending limb [7]
• Both effects were prevented by the
• Beta3-AR antagonist L748,337
• protein kinase A inhibitor H89 [7]

Genetic inactivation of beta3-AR in mice

• Associated with significantly increased urine excretion of water, sodium, potassium, and chloride [7]

Stimulation of beta3-AR significantly

• Reduced urine excretion of water and the same electrolytes [7]

BRL37344 (agonista) promoted

• Potent antidiuretic effect in AVPR2-null mice [7]

Může zhoršovat/dělat otoky nohou ?

Metabolické účinky

• Increase lipolysis
• Incr. fat oxidation
• Incr. energy expenditure
• Incr. insulin action
• Might serve as an attractive target for the treatment of diabetes and obesity
• In vivo stimulation of this receptor by selective agonists
• Lead to glycemic improvements
• Weight loss in rodent models of diabetes and obesity
• Research largely unsuccessful to date
• Pharmacological differences between the rodent and human beta(3)-AR
• Lack of selectivity of previous compounds for the beta(3)-AR over beta(1)-/beta(2)-ARs
• Unsatisfactory oral bioavailability pharmacokinetic properties

Lokalizace beta 3 AR

Smooth muscle cells in the urinary bladder express beta 3-AR

• Effect on the detrusor muscle which relaxes when the beta 3-AR are activated
• Relaxed detrusor muscle improves filling capacity of the bladder
• Eases the urge to pass urine [1]

Aha ! Ve stresové situaci pod vlivem noradrenalinu a adrenalinu zajistí, že močový měchýř nás nebude zbytečně obtěžovat při boji nebo útěku.

• Cellular and messenger RNA expression studies have identified that majority of the beta-adrenergic receptors in the human detrusor muscle are of the beta-3 subtype,
• Found to promote detrusor relaxation
• Aid urine storage (Fujimura 1999; Takeda 1999)
• Several randomised controlled trials have shown significant reduction of OAB symptoms among patients with moderate to severe symptoms
• Over at least an eight-week treatment period with beta-adrenergic receptor agonists (Ohlstein 2012)
• Dose-dependent improvement (reduction) in the number of micturition episodes
• With good safety and tolerability (Chapple 2013a; Chapple 2013b; Chapple 2013c; Khullar 2013)
• Efficacy and safety in controlling OAB symptoms on outcomes such as frequency and incontinence
• Fewer incidences of the antimuscarinic side effects such as
• Dry mouth
• Constipation compared to placebo and other drugs (Medscape 2013; Sacco 2012)
• Adverse effects in some particular types of beta-3 adrenergic receptor agonists (FDA 2012; Nitti 2013)
• Hypertension
• Nasopharyngitis
• Urinary tract infection
• Headache [12]

Svalovina

• Appear to coexist with beta 2 adrenoceptors in skeletal muscle, where the latter predominate [PMID: 2565118] [10]

Termogeneze

• Beta 3-AR has been linked to thermogenesis in human skeletal muscles
• Studies showing it to be responsible for over 40% of ephedrine-induced thermogenesis [1]