alpha-1 (α1) adrenergic receptors are G protein-coupled receptors (GPCRs) associated with the Gq heterotrimeric G protein. α1-adrenergic receptors are subdivided into three highly homologous subtypes, i.e., α1A-, α1B-, and α1D-adrenergic receptor subtypes. 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. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α1-adrenergic receptors in the central and peripheral nervous systems. The crystal structure of the α1B-adrenergic receptor subtype has been determined in complex with the inverse agonist (+)-cyclazosin.[2]

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.[3] The neurotransmitter norepinephrine has higher affinity for the α1 receptor than does the hormone adrenaline.

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[4] of gastrointestinal system, kidney (renal artery)[5] and brain.[6] 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 internal urethral sphincter[7] of the urinary bladder,[8][9] 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.[10] 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.[11] Norepinephrine also stimulates serotonin release by binding α1-adrenergic receptors located on serotonergic neurons in the raphe.[12] α1-adrenergic receptor subtypes increase inhibition in the olfactory system, suggesting a synaptic mechanism for noradrenergic modulation of olfactory driven behaviors.[13]

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 phosphatidylinositol to be transformed into inositol trisphosphate (IP3) and diacylglycerol (DAG). While DAG stays near the membrane, IP3 diffuses into the cytosol and to find the IP3 receptor on the endoplasmic reticulum, triggering calcium release from the stores. 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.[18] 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.[18]

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 RM, Perez DM, Hwa J, Piascik MT (May 1996). "alpha 1-adrenergic receptor subtypes. Molecular structure, function, and signaling". Circulation Research. 78 (5): 737–49. doi:10.1161/01.RES.78.5.737. PMID 8620593.
  2. ↑ Deluigi M, Morstein L, Schuster M, Klenk C, Merklinger L, Cridge RR, de Zhang LA, Klipp A, Vacca S, Vaid TM, Mittl PR, Egloff P, Eberle SA, Zerbe O, Chalmers DK, Scott DJ, Plückthun A (January 2022). "Crystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition". Nature Communications. 13 (1): 382. Bibcode:2022NatCo..13..382D. doi:10.1038/s41467-021-27911-3. PMC 8770593. PMID 35046410.
  3. ↑ Piascik MT, Perez DM (August 2001). "Alpha1-adrenergic receptors: new insights and directions". The Journal of Pharmacology and Experimental Therapeutics. 298 (2): 403–10. PMID 11454900.
  4. 1 2 3 Rang HP (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4. Page 163
  5. ↑ Schmitz JM, Graham RM, Sagalowsky A, Pettinger WA (November 1981). "Renal alpha-1 and alpha-2 adrenergic receptors: biochemical and pharmacological correlations". The Journal of Pharmacology and Experimental Therapeutics. 219 (2): 400–6. PMID 6270306.
  6. ↑ Circulation & Lung Physiology I Archived 2011-07-26 at the Wayback Machine M.A.S.T.E.R. Learning Program, UC Davis School of Medicine
  7. ↑ Le, Tao; Bhushan, Vikas; Sochat, Matthew (2021). First Aid for the USMLE Step 1 2021:A Student to Student Guide. McGraw Hill. p. 240. ISBN 978-1-260-46752-9.
  8. 1 2 3 4 5 Fitzpatrick D, Purves D, Augustine G (2004). "Table 20:2". Neuroscience (3rd ed.). Sunderland, Mass: Sinauer. ISBN 978-0-87893-725-7.
  9. ↑ Chou EC, Capello SA, Levin RM, Longhurst PA (December 2003). "Excitatory alpha1-adrenergic receptors predominate over inhibitory beta-receptors in rabbit dorsal detrusor". The Journal of Urology. 170 (6 Pt 1): 2503–7. doi:10.1097/01.ju.0000094184.97133.69. PMID 14634460.
  10. ↑ Cheng JT, Kuo DY (August 2003). "Both alpha1-adrenergic and D(1)-dopaminergic neurotransmissions are involved in phenylpropanolamine-mediated feeding suppression in mice". Neuroscience Letters. 347 (2): 136–8. doi:10.1016/S0304-3940(03)00637-2. PMID 12873745. S2CID 24284964.
  11. ↑ Dinh L, Nguyen T, Salgado H, Atzori M (November 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". Neurochemical Research. 34 (11): 1896–906. doi:10.1007/s11064-009-9966-z. PMID 19357950. S2CID 25255160.
  12. ↑ Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved October 20, 2020 from https://stahlonline-cambridge-org.offcampus.lib.washington.edu/essential_4th_chapter.jsf?page=chapter7.htm&name=Chapter%207&title=Antidepressant%20classes#c02598-7-76
  13. ↑ Zimnik NC, Treadway T, Smith RS, Araneda RC (April 2013). "α(1A)-Adrenergic regulation of inhibition in the olfactory bulb". The Journal of Physiology. 591 (7): 1631–43. doi:10.1113/jphysiol.2012.248591. PMC 3624843. PMID 23266935.
  14. ↑ Wang GY, McCloskey DT, Turcato S, Swigart PM, Simpson PC, Baker AJ (October 2006). "Contrasting inotropic responses to alpha1-adrenergic receptor stimulation in left versus right ventricular myocardium". American Journal of Physiology. Heart and Circulatory Physiology. 291 (4): H2013-7. doi:10.1152/ajpheart.00167.2006. PMID 16731650. S2CID 20464280.
  15. ↑ Moro C, Tajouri L, Chess-Williams R (January 2013). "Adrenoceptor function and expression in bladder urothelium and lamina propria". Urology. 81 (1): 211.e1–7. doi:10.1016/j.urology.2012.09.011. PMID 23200975.
  16. 1 2 Boron WF (2005). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. ISBN 978-1-4160-2328-9. Page 787
  17. ↑ Tadjalli A, Duffin J, Peever J (December 2010). "Identification of a novel form of noradrenergic-dependent respiratory motor plasticity triggered by vagal feedback". The Journal of Neuroscience. 30 (50): 16886–95. doi:10.1523/JNEUROSCI.3394-10.2010. PMC 6634916. PMID 21159960.
  18. 1 2 Buckwalter JB, Naik JS, Valic Z, Clifford PS (January 2001). "Exercise attenuates alpha-adrenergic-receptor responsiveness in skeletal muscle vasculature". Journal of Applied Physiology. 90 (1): 172–8. doi:10.1152/jappl.2001.90.1.172. PMID 11133908. S2CID 71048990.
  19. ↑ Fahed S, Grum DF, Papadimos TJ (May 2008). "Labetalol infusion for refractory hypertension causing severe hypotension and bradycardia: an issue of patient safety". Patient Safety in Surgery. 2: 13. doi:10.1186/1754-9493-2-13. PMC 2429901. PMID 18505576.
  20. ↑ 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. doi:10.1021/jm00370a011. PMID 6142954.
  • "Adrenoceptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
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