View source for Alpha-1 adrenergic receptor

{{Short description|G protein-coupled receptor}}
{{See also|Adrenergic receptor}}

'''alpha-1''' ('''α<sub>1</sub>''') '''adrenergic ''' are [[G protein-coupled receptors]] (GPCRs) associated with the [[Gq alpha subunit|G<sub>q</sub>]] [[heterotrimeric G protein]]. α<sub>1</sub>-adrenergic receptors are subdivided into three highly homologous subtypes, i.e., [[α1A-adrenergic|α<sub>1A</sub>-]], [[α1B-adrenergic|α<sub>1B</sub>-]], and [[α1D-adrenergic|α<sub>1D</sub>-adrenergic]] receptor subtypes. There is no α<sub>1C</sub> receptor. At one time, there was a subtype known as α<sub>1C</sub>, but it was found to be identical to the previously discovered α<sub>1A</sub> receptor subtype.<ref>{{cite journal | vauthors = Graham RM, Perez DM, Hwa J, Piascik MT | title = alpha 1-adrenergic receptor subtypes. Molecular structure, function, and signaling | journal = Circulation Research | volume = 78 | issue = 5 | pages = 737–49 | date = May 1996 | pmid = 8620593 | doi = 10.1161/01.RES.78.5.737 | url = http://circres.ahajournals.org/content/78/5/737 | url-access = subscription }}</ref> To avoid confusion, naming was continued with the letter D. [[Catecholamine]]s like [[norepinephrine]] (noradrenaline) and [[epinephrine]] (adrenaline) signal through the α<sub>1</sub>-adrenergic receptors in the [[central nervous system|central]] and [[peripheral nervous system]]s. The crystal structure of the α<sub>1B</sub>-adrenergic receptor subtype has been determined in complex with the inverse agonist (+)-cyclazosin.<ref name="pmid=35046410">{{cite journal |vauthors=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 |title=Crystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition |journal=Nature Communications |volume=13 |issue=1 |pages=382 |date=January 2022 |doi=10.1038/s41467-021-27911-3 |pmid=35046410 |pmc=8770593 |bibcode=2022NatCo..13..382D |doi-access=free }}</ref>

==Effects==
The α<sub>1</sub>-adrenergic receptor has several general functions in common with the [[Alpha-2 adrenergic receptor|α<sub>2</sub>-adrenergic receptor]], but also has specific effects of its own. α<sub>1</sub>-receptors primarily mediate [[Smooth muscle tissue|smooth muscle]] contraction, but have important functions elsewhere as well.<ref>{{cite journal | vauthors = Piascik MT, Perez DM | title = Alpha1-adrenergic receptors: new insights and directions | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 298 | issue = 2 | pages = 403–10 | date = August 2001 | pmid = 11454900 }}</ref>  The [[neurotransmitter]] norepinephrine has higher affinity for the α<sub>1</sub> receptor than does the hormone [[adrenaline]].

===Smooth muscle===
In smooth muscle cells of [[blood vessel]]s the principal effect of activation of these receptors is [[vasoconstriction]]. Blood vessels with α<sub>1</sub>-adrenergic receptors are present in the [[skin]], the [[sphincters]]<ref name=Rang163/> of [[gastrointestinal system]], [[kidney]] ([[renal artery]])<ref name="pmid6270306">{{cite journal | vauthors = Schmitz JM, Graham RM, Sagalowsky A, Pettinger WA | title = Renal alpha-1 and alpha-2 adrenergic receptors: biochemical and pharmacological correlations | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 219 | issue = 2 | pages = 400–6 | date = November 1981 | pmid = 6270306 | url = http://jpet.aspetjournals.org/cgi/content/abstract/219/2/400 }}</ref> and [[brain]].<ref>[http://cim.ucdavis.edu/masters/sessions2002/session4_ica.doc Circulation & Lung Physiology I] {{Webarchive|url=https://web.archive.org/web/20110726230145/http://cim.ucdavis.edu/masters/sessions2002/session4_ica.doc |date=2011-07-26 }} M.A.S.T.E.R. Learning Program, UC Davis School of Medicine</ref> 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<ref name=firstaid>{{cite book|last1=Le |first1=Tao |last2=Bhushan |first2=Vikas |last3=Sochat |first3=Matthew |date=2021 |title=First Aid for the USMLE Step 1 2021:A Student to Student Guide|publisher=McGraw Hill |page=240 |isbn=978-1-260-46752-9}}</ref> of the [[urinary bladder]],<ref name="purves">{{cite book | last1 = Fitzpatrick | first1 = David  | last2 = Purves | first2 = Dale | last3 = Augustine | first3 = George | name-list-style = vanc |title=Neuroscience |publisher=Sinauer |location=Sunderland, Mass |year=2004 |edition=3rd |chapter=Table 20:2 |isbn=978-0-87893-725-7 }}</ref><ref name="pmid14634460">{{cite journal | vauthors = Chou EC, Capello SA, Levin RM, Longhurst PA | title = Excitatory alpha1-adrenergic receptors predominate over inhibitory beta-receptors in rabbit dorsal detrusor | journal = The Journal of Urology | volume = 170 | issue = 6 Pt 1 | pages = 2503–7 | date = December 2003 | pmid = 14634460 | doi = 10.1097/01.ju.0000094184.97133.69 }}</ref> although this effect is minor compared to the relaxing effect of [[Beta-2 adrenergic receptor|β<sub>2</sub>-adrenergic receptor]]s. 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:
* [[Ureter]]
* [[Uterus]] (when pregnant): this is minor compared to the relaxing effects of the β<sub>2</sub> receptor, agonists of which{{emdash}}notably albuterol/salbutamol{{emdash}}were formerly{{Citation needed|date=June 2019}} used to inhibit premature labor.
* [[Urethral sphincter]]
* [[Bronchioles]] (although minor to the relaxing effect of β<sub>2</sub> receptor on bronchioles)
* [[Iris dilator muscle]]<ref name=Rang163>{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |isbn=978-0-443-07145-4 }} Page 163</ref>
* [[Seminal tract]],<ref name=Rang163/> resulting in [[ejaculation]]

===Neuronal===
Activation of α<sub>1</sub>-adrenergic receptors produces [[anorexia (symptom)|anorexia]] and partially mediates the efficacy of [[Anorectic|appetite suppressants]] like [[phenylpropanolamine]] and [[amphetamine]] in the treatment of [[obesity]].<ref name=pmid12873745>{{cite journal | vauthors = Cheng JT, Kuo DY | title = Both alpha1-adrenergic and D(1)-dopaminergic neurotransmissions are involved in phenylpropanolamine-mediated feeding suppression in mice | journal = Neuroscience Letters | volume = 347 | issue = 2 | pages = 136–8 | date = August 2003 | pmid = 12873745 | doi = 10.1016/S0304-3940(03)00637-2 | s2cid = 24284964 }}</ref> Norepinephrine has been shown to decrease [[Membrane potential|cellular excitability]] in all layers of the [[temporal cortex]], including the [[primary auditory cortex]]. In particular, norepinephrine decreases [[Glutamic acid|glutamatergic]] excitatory [[postsynaptic potential]]s by the activation of α<sub>1</sub>-adrenergic receptors.<ref name=Dinh2009>{{cite journal | vauthors = Dinh L, Nguyen T, Salgado H, Atzori M | title = 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 | journal = Neurochemical Research | volume = 34 | issue = 11 | pages = 1896–906 | date = November 2009 | pmid = 19357950 | doi = 10.1007/s11064-009-9966-z | s2cid = 25255160 }}</ref> Norepinephrine also stimulates [[serotonin]] release by binding α<sub>1</sub>-adrenergic receptors located on serotonergic neurons in the raphe.<ref>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</ref>
α<sub>1</sub>-adrenergic receptor subtypes increase inhibition in the olfactory system, suggesting a synaptic mechanism for noradrenergic modulation of olfactory driven behaviors.<ref name="pmid23266935">{{cite journal | vauthors = Zimnik NC, Treadway T, Smith RS, Araneda RC | title = α(1A)-Adrenergic regulation of inhibition in the olfactory bulb | journal = The Journal of Physiology | volume = 591 | issue = 7 | pages = 1631–43 | date = April 2013 | pmid = 23266935 | pmc = 3624843 | doi = 10.1113/jphysiol.2012.248591 }}</ref>

===Other===

* Both positive and negative [[inotropic]] effects on [[heart muscle]]<ref name=purves/><ref>{{cite journal | vauthors = Wang GY, McCloskey DT, Turcato S, Swigart PM, Simpson PC, Baker AJ | title = Contrasting inotropic responses to alpha1-adrenergic receptor stimulation in left versus right ventricular myocardium | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 291 | issue = 4 | pages = H2013-7 | date = October 2006 | pmid = 16731650 | doi = 10.1152/ajpheart.00167.2006 | s2cid = 20464280 }}</ref>
* Secretion from [[salivary gland]]<ref name=purves/>
* Increase salivary [[potassium]] levels
* [[Glycogenolysis]] and [[gluconeogenesis]] in [[liver]].
* Secretion from [[sweat gland]]s<ref name=purves/>
* Contraction of the urinary bladder urothelium and lamina propria <ref name="Moro et al. 2013">{{cite journal | vauthors = Moro C, Tajouri L, Chess-Williams R | title = Adrenoceptor function and expression in bladder urothelium and lamina propria | journal = Urology | volume = 81 | issue = 1 | pages = 211.e1–7 | date = January 2013 | pmid = 23200975 | doi = 10.1016/j.urology.2012.09.011 }}</ref> 
* [[Sodium|Na<sup>+</sup>]] reabsorption from [[kidney]]<ref name=purves/>
** Stimulate [[proximal tubule]] [[NHE3]]<ref name=boron787>{{cite book | vauthors = Boron WF |title=Medical Physiology: A Cellular And Molecular Approaoch |publisher=Elsevier/Saunders |year=2005 |isbn=978-1-4160-2328-9 }} Page 787</ref>
** Stimulate [[proximal tubule]] basolateral [[Na-K ATPase]]<ref name=boron787/>
* Activate [[mitogenic]] responses and regulate growth and proliferation of many cells
* Involved in the detection of mechanical feedback on the [[hypoglossal nucleus|hypoglossal]] motor neurons which allow a long-term facilitation in respiration in response to repeated [[apnea]]s.<ref>{{cite journal | vauthors = Tadjalli A, Duffin J, Peever J | title = Identification of a novel form of noradrenergic-dependent respiratory motor plasticity triggered by vagal feedback | journal = The Journal of Neuroscience | volume = 30 | issue = 50 | pages = 16886–95 | date = December 2010 | pmid = 21159960 | pmc = 6634916 | doi = 10.1523/JNEUROSCI.3394-10.2010 | doi-access = free }}</ref>

==Signaling cascade==
α<sub>1</sub>-Adrenergic receptors are members of the [[G protein-coupled receptor]] superfamily. Upon activation, a [[heterotrimeric G protein]], [[Gq alpha subunit|G<sub>q</sub>]], activates [[phospholipase C]] (PLC), which causes [[phosphatidylinositol]] to be transformed into [[inositol trisphosphate|inositol trisphosphate (IP<sub>3</sub>)]] and [[Diglyceride|diacylglycerol (DAG)]]. While DAG stays near the membrane, IP<sub>3</sub> diffuses into the cytosol and to find the IP<sub>3</sub> 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, α<sub>1</sub>-adrenergic receptors in active muscles are attenuated in an exercise intensity-dependent manner, allowing the β<sub>2</sub>-adrenergic receptors which mediate vasodilation to dominate.<ref name=":1">{{cite journal | vauthors = Buckwalter JB, Naik JS, Valic Z, Clifford PS | title = Exercise attenuates alpha-adrenergic-receptor responsiveness in skeletal muscle vasculature | journal = Journal of Applied Physiology | volume = 90 | issue = 1 | pages = 172–8 | date = January 2001 | pmid = 11133908 | doi = 10.1152/jappl.2001.90.1.172 | s2cid = 71048990 }}</ref> In contrast to α<sub>2</sub>-adrenergic receptors, α<sub>1</sub>-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.<ref name=":1" />

Note that only active muscle α<sub>1</sub>-adrenergic receptors will be blocked. Resting muscle will not have its α<sub>1</sub>-adrenergic receptors blocked, and hence the overall effect will be α<sub>1</sub>-adrenergic-mediated vasoconstriction.{{Citation needed|date=May 2011}}

==Ligands==
{{Main|Alpha-1 blocker}}{{col-begin}}
{{col-2}}
; Agonists
* [[Cirazoline]] ([[vasoconstrictor]])
* [[Methoxamine]] ([[vasoconstrictor]])
* [[Synephrine]] (mild [[vasoconstrictor]])
* [[Etilefrine]] ([[antihypotensive]])
* [[Metaraminol]] ([[antihypotensive]])
* [[Midodrine]] ([[antihypotensive]])
* [[Naphazoline]] ([[decongestant]])
* [[Norepinephrine]] ([[vasoconstrictor]])
* [[Oxymetazoline]] ([[decongestant]])
* [[Phenylephrine]] ([[decongestant]])
* [[Pseudoephedrine]] ([[decongestant]])
* [[Tetrahydrozoline]] ([[decongestant]])
* [[Xylometazoline]] ([[decongestant]])
*[https://pubchem.ncbi.nlm.nih.gov/compound/128503 Sdz-nvi-085] [104195-17-7].
{{col-2}}
; Antagonists
* [[Acepromazine]] (antipsychotic, secondary mechanism)
* [[Alfuzosin]] (used in [[benign prostatic hyperplasia]])
* [[Arotinolol]]
* [[Carvedilol]] (used in [[congestive heart failure]]; it is a non-selective beta blocker)
* [[Chlorpromazine]] (antipsychotic and powerful antihypertensive)
* [[Doxazosin]] (used in [[hypertension]] and benign prostatic hyperplasia)
* [[Indoramin]]
* [[Labetalol]] (used in [[hypertension]]; it is a mixed alpha/beta adrenergic antagonist)<ref name="pmid18505576">{{cite journal | vauthors = Fahed S, Grum DF, Papadimos TJ | title = Labetalol infusion for refractory hypertension causing severe hypotension and bradycardia: an issue of patient safety | journal = Patient Safety in Surgery | volume = 2 | pages = 13 | date = May 2008 | pmid = 18505576 | pmc = 2429901 | doi = 10.1186/1754-9493-2-13 | doi-access = free }}</ref>
* [[Moxisylyte]]
* [[Phenoxybenzamine]]
* [[Phentolamine]] (used in [[hypertensive emergencies]]; it is a nonselective alpha-antagonist)
* [[Prazosin]] (used in hypertension)
* [[Quetiapine]]
* [[Risperidone]]
* [[Silodosin]]
* [[Tamsulosin]] (used in benign prostatic hyperplasia)
* [[Terazosin]]
* [[Tiamenidine]]<ref>{{cite journal | vauthors = Timmermans PB, de Jonge A, Thoolen MJ, Wilffert B, Batink H, van Zwieten PA | title = Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists | journal = Journal of Medicinal Chemistry | volume = 27 | issue = 4 | pages = 495–503 | date = April 1984 | pmid = 6142954 | doi = 10.1021/jm00370a011 }}</ref>
* [[Tolazoline]]
* [[Trazodone]]
* [[Trimazosin]]
* [[Urapidil]]
{{col-end}}

Various [[heterocyclic]] [[antidepressant]]s and [[antipsychotic]]s are α<sub>1</sub>-adrenergic receptor antagonists as well. This action is generally undesirable in such agents and mediates [[side effect]]s like [[orthostatic hypotension]], and headaches due to excessive vasodilation.

== See also ==
* [[Adrenergic receptor]]

== References ==
{{Reflist|2}}

== External links ==
* {{cite web |url=http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1274 |title=Adrenoceptors  |work= IUPHAR Database of Receptors and Ion Channels |publisher=International Union of Basic and Clinical Pharmacology }}

{{G protein-coupled receptors}}
{{Adrenergics}}

[[Category:Adrenergic receptors]]
[[Category:Exercise biochemistry]]