Alpha-1 adrenergic receptor

The alpha-1 (α1) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α1-adrenergic receptor in the central and peripheral nervous systems. There is no α1C receptor. At one time, there was a subtype known as α1C, but it was found to be identical to the previously discovered α1A receptor subtype.[1] To avoid confusion, naming was continued with the letter D.

Effects

The α1-adrenergic receptor has several general functions in common with the α2-adrenergic receptor, but also has specific effects of its own. α1-receptors primarily mediate smooth muscle contraction, but have important functions elsewhere as well.[2] The neurotransmitter noradrenaline has higher affinity for the α1 receptor than does adrenaline (which is a hormone).

Smooth muscle

In smooth muscle cells of blood vessels the principal effect of activation of these receptors is vasoconstriction. Blood vessels with α1-adrenergic receptors are present in the skin, the sphincters[3] of gastrointestinal system, kidney (renal artery)[4] and brain.[5] During the fight-or-flight response vasoconstriction results in decreased blood flow to these organs. This accounts for the pale appearance of the skin of an individual when frightened.

It also induces contraction of the urinary bladder,[6][7] although this effect is minor compared to the relaxing effect of β2-adrenergic receptors. In other words, the overall effect of sympathetic stimuli on the bladder is relaxation, in order to inhibit micturition upon anticipation of a stressful event. Other effects on smooth muscle are contraction in:

Neuronal

Activation of α1-adrenergic receptors produces anorexia and partially mediates the efficacy of appetite suppressants like phenylpropanolamine and amphetamine in the treatment of obesity.[8] Norepinephrine has been shown to decrease cellular excitability in all layers of the temporal cortex, including the primary auditory cortex. In particular, norepinephrine decreases glutamatergic excitatory postsynaptic potentials by the activation of α1-adrenergic receptors.[9] α1-adrenergic receptor subtypes increase inhibition in the olfactory system, suggesting a synaptic mechanism for noradrenergic modulation of olfactory driven behaviors.[10]

Other

Signaling cascade

α1-Adrenergic receptors are members of the G protein-coupled receptor superfamily. Upon activation, a heterotrimeric G protein, Gq, activates phospholipase C (PLC), which causes an increase in IP3 and calcium. This triggers further effects, primarily through the activation of an enzyme Protein Kinase C. This enzyme, as a kinase, functions by phosphorylation of other enzymes causing their activation, or by phosphorylation of certain channels leading to the increase or decrease of electrolyte transfer in or out of the cell.

Activity during exercise

During exercise, α1-adrenergic receptors in active muscles are attenuated in an exercise intensity-dependent manner, allowing the β2-adrenergic receptors which mediate vasodilation to dominate.[15] In contrast to α2-adrenergic receptors, α1-adrenergic-receptors in the arterial vasculature of skeletal muscle are more resistant to inhibition, and attenuation of α1-adrenergic-receptor-mediated vasoconstriction only occurs during heavy exercise.[15]

Note that only active muscle α1-adrenergic receptors will be blocked. Resting muscle will not have its α1-adrenergic receptors blocked, and hence the overall effect will be α1-adrenergic-mediated vasoconstriction.

Ligands

Various heterocyclic antidepressants and antipsychotics are α1-adrenergic receptor antagonists as well. This action is generally undesirable in such agents and mediates side effects like orthostatic hypotension, and headaches due to excessive vasodilation.

See also

References

  1. ↑ Graham, Robert (May 1, 1996). "α1-Adrenergic Receptor Subtypes Molecular Structure, Function, and Signaling". Circulation Research. 78 (5): 737–749. doi:10.1161/01.RES.78.5.737. Retrieved 6 December 2016.
  2. ↑ Piascik, M. T.; Perez, D. M. (2001). "Alpha1-adrenergic receptors: New insights and directions". The Journal of Pharmacology and Experimental Therapeutics. 298 (2): 403–10. PMID 11454900.
  3. 1 2 3 Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 163
  4. ↑ Schmitz JM, Graham RM, Sagalowsky A, Pettinger WA (1981). "Renal α1 and α2 adrenergic receptors: biochemical and pharmacological correlations". J. Pharmacol. Exp. Ther. 219 (2): 400–6. PMID 6270306.
  5. ↑ Circulation & Lung Physiology I M.A.S.T.E.R. Learning Program, UC Davis School of Medicine
  6. 1 2 3 4 5 Fitzpatrick, David; Purves, Dale; Augustine, George (2004). "Table 20:2". Neuroscience (3rd ed.). Sunderland, Mass: Sinauer. ISBN 0-87893-725-0.
  7. ↑ Chou EC, Capello SA, Levin RM, Longhurst PA (2003). "Excitatory α1-adrenergic receptors predominate over inhibitory β-receptors in rabbit dorsal detrusor". J. Urol. 170 (6 Pt 1): 2503–7. PMID 14634460. doi:10.1097/01.ju.0000094184.97133.69.
  8. ↑ Cheng JT, Kuo DY (2003). "Both alpha1-adrenergic and D(1)-dopaminergic neurotransmissions are involved in phenylpropanolamine-mediated feeding suppression in mice". Neuroscience Letters. 347 (2): 136–8. PMID 12873745. doi:10.1016/S0304-3940(03)00637-2.
  9. ↑ Dinh, L; Nguyen T; Salgado H; Atzori M (2009). "Norepinephrine homogeneously inhibits alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate- (AMPAR-) mediated currents in all layers of the temporal cortex of the rat". Neurochem Res. 34 (11): 1896–906. PMID 19357950. doi:10.1007/s11064-009-9966-z.
  10. ↑ Zimnik NC, Treadway T, Smith RS, Araneda RC (2013). "α(1A)-Adrenergic regulation of inhibition in the olfactory bulb". J. Physiol. (Lond.). 591 (Pt 7): 1631–43. PMC 3624843 Freely accessible. PMID 23266935. doi:10.1113/jphysiol.2012.248591.
  11. ↑ Wang, G. Y.; McCloskey, D. T.; Turcato, S; Swigart, P. M.; Simpson, P. C.; Baker, A. J. (2006). "Contrasting inotropic responses to alpha1-adrenergic receptor stimulation in left versus right ventricular myocardium". AJP: Heart and Circulatory Physiology. 291 (4): H2013–7. PMID 16731650. doi:10.1152/ajpheart.00167.2006.
  12. ↑ Moro C, Tajouri L, Chess-Williams R (Jan 2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology. 81 (1): 211.e1–7. PMID 23200975. doi:10.1016/j.urology.2012.09.011.
  13. 1 2 Walter F. Boron (2005). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 1-4160-2328-3. Page 787
  14. ↑ Tadjalli, Arash; Duffin, James; Peever, John (2010). "Identification of a novel form of noradrenergic-dependent respiratory motor plasticity triggered by vagal feedback". The Journal of Neuroscience. 30 (50): 16886–16895. PMID 21159960. doi:10.1523/JNEUROSCI.3394-10.2010.
  15. 1 2 http://jap.physiology.org/content/90/1/172.full
  16. ↑ Fahed S, Grum DF, Papadimos TJ (2008). "Labetalol infusion for refractory hypertension causing severe hypotension and bradycardia: an issue of patient safety". Patient Saf Surg. 2: 13. PMC 2429901 Freely accessible. PMID 18505576. doi:10.1186/1754-9493-2-13.
  17. ↑ Timmermans, PB; de Jonge, A; Thoolen, MJ; Wilffert, B; Batink, H; van Zwieten, PA (April 1984). "Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.". Journal of Medicinal Chemistry. 27 (4): 495–503. PMID 6142954. doi:10.1021/jm00370a011.
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