Mokhoa oa Liketso oa Adrenergic Receptor
Li-receptor tsa Adrenergic ke li-receptor tse arabelang ho catecholamines—haholo-holo adrenaline (epinephrine) le noradrenaline (norepinephrine)—'me ke karolo ea bohlokoa ea tsamaiso ea methapo ea kutlo. Ho kengoa tšebetsong ha li-receptor tsena ho lumella' mele ho ikamahanya le maemo a fapaneng, haholo-holo maemo a "ntoa kapa a ho baleha" joalo ka khatello ea maikutlo, boikoetliso ba 'mele, tšabo, kapa maemo a tšohanyetso. Ho ea ka 'mele, li-receptor tsa adrenergic li bapala karolo ea ho laola sekhahla sa pelo le matla a ho honyela, bophara ba methapo ea mali, molumo oa bronchial, glucose le metabolism ea mafura, esita le likarabelo tsa mahlo le tsa mala. Ho utloisisa mekhoa ea ts'ebetso ea li-receptor tsa adrenergic ha ho bohlokoa feela bakeng sa saense ea motheo empa hape le bakeng sa ts'ebetso ea bongaka, kaha lithethefatsi tse ngata li sebetsa ka ho hlasimolla (agonist) kapa ho thibela (antagonist) li-receptor tsena.
1. Mefuta le libaka tsa li-receptor tsa adrenergic
Li-receptor tsa adrenergic ka kakaretso li arotsoe ka lihlopha tse peli tse kholo: li-receptor tsa alpha (α) le beta (β), tse arotsoeng hape ka mefuta e fapaneng.
1. Li-receptor tsa α1: li fumanoa ka bongata mesifeng e boreleli ea methapo ea mali (vasoconstriction), mesifeng ea radial ea iris (mydriasis), li-sphincters tsa moroto, le lisele tse ling tsa sebete.
2. Li-receptor tsa α2: li fumanoa ka bongata lipheletsong tsa methapo ea presynaptic (e le "brake" ha neurotransmitter e lokolloa), li fumaneha hape liplateleteng, manyemeng le methapong e meng ea mali.
3. Li-receptor tsa β1: li laola pelo (ho eketsa maqhubu, ho tsamaisa le ho honyela), hammoho le liseleng tsa juxtaglomerular tsa liphio (ho eketsa renin).
4. Li-receptor tsa β2: li fumanoa ka bongata ho bronchi (bronchodilation), methapo ea mali ea mesifa ea masapo (vasodilation), popelo (relaxation), le mesifa ea sebete le ea masapo (metabolism).
5. Li-receptor tsa β3: haholo-holo liseleng tsa mafura (lipolysis) le senya (ho phomola ha detrusor).
Seamoheli se seng le se seng se na le phello e fapaneng hobane se hokahane le tsela e itseng ea phetisetso ea lets'oao ka hare ho sele.
2. Melao-motheo e akaretsang ea mekhoa ea ho sebetsa: GPCR le phetisetso ea lets'oao
Bongata ba li-receptor tsa adrenergic ke tsa lelapa la li-receptor tse kopantsoeng ke protheine ea G (GPCR), tse nang le libaka tse supileng tsa transmembrane. Ha adrenaline kapa noradrenaline e tlama ho receptor, ho etsahala phetoho ea sebopeho e kenyang tšebetsong protheine ea G ea ka hare ho sele. Liprotheine tsa G li entsoe ka li-subunit tse tharo: α, β, le γ. Boemong ba phomolo, subunit ea α e tlama GDP. Ha receptor e kentsoe tšebetsong:
1. GDP ho subunit ea α e nkeloa sebaka ke GTP
2. Karoloana e nyenyane ea α e lokolloa (hammoho le GTP) ho tsoa ho βγ complex.
3. Karoloana e nyenyane ea α-GTP le/kapa βγ e ntan'o kenya tšebetsong kapa ho thibela kanale ea effector enzyme/ion.
4. Letšoao le holisoa ka ho thehoa ha baromuwa ba bobeli ba kang cAMP kapa IP3/DAG.
5. Qetellong, ho na le diphetoho tshebetsong ya protheine (ka phosphorylation) le diphetoho tshebetsong ya sele (ho honyela, ho phomola, ho ntsha secretion, metabolism).
Letšoao le fela ha α subunit e fetola GTP ho GDP (mosebetsi oa GTPase oa kahare), ebe e kopana hape le βγ. Ho feta moo, receptor e ka feta ho fokotseng kutloisiso ka phosphorylation le internalization.
3. Mokhoa oa receptor oa α1: Tsela ea Gq – IP3/DAG le Ca²⁺ e eketsehileng
Seamoheli sa α1 se hokahantsoe le protheine ea G ea mofuta oa G. Ho kengoa tšebetsong ha α1 ho hlohlelletsa enzyme phospholipase C (PLC), e qhaqhang membrane phospholipids (PIP2) hore e be messengers tse peli tsa metsotsoana:
– IP3 (inositol trisphosphate): e baka ho lokolloa ha Ca²⁺ ho tsoa ho endoplasmic/sarcoplasmic reticulum.
– DAG (diacylglycerol): e kenya tshebetsong protheine kinase C (PKC)
Keketseho ea Ca²⁺ ka hare ho sele ke senotlolo sa karabelo ea α1, haholo-holo mesifa e boreleli. Ca²⁺ e tlama ho calmodulin 'me e kenya tšebetsong myosin light chain kinase (MLCK), e etsang hore liketane tsa leseli tsa myosin li be le phosphorylation, e leng se bakang ho honyela ha mesifa e boreleli. Ka hona, ts'ebetso ea α1 hangata e fella ka ho honyela ha methapo ea mali (ho hanyetsa ho eketsehileng ha methapo le khatello ea mali), ho honyela ha sphincter, le mydriasis.
Ka bongaka, li-agonist tsa α1 (mohlala, phenylephrine) li sebelisoa bakeng sa meriana e fokotsang ho ruruha le ho eketsa khatello ea mali, ha li-antagonist tsa α1 (mohlala, prazosin, tamsulosin) li sebelisoa bakeng sa khatello e phahameng ea mali kapa matšoao a BPH.
4. Mokhoa oa receptor oa α2: Tsela ea Gi - ho fokotseha ha cAMP le thibelo ea ho lokolloa ha neurotransmitter
Seamoheli sa α2 haholo-holo se tsamaisana le liprotheine tsa G tsa mofuta oa Gi (tse thibelang). Ho kengoa tšebetsong ha α2 ho tla:
– E thibela adenylate cyclase → e fokotsa tlhahiso ea cAMP
– E fokotsa mosebetsi oa protheine kinase A (PKA)
– Ho li-neuron tsa presynaptic, α2 e ka boela ea bula likanale tsa K⁺ le ho koala likanale tsa Ca²⁺, ka hona e fokotsa phallo ea Ca²⁺ nakong ea matla a ketso.
Ho kenella ha Ca²⁺ ka har'a terminal ea presynaptic ho bohlokoa bakeng sa ho lokolloa ha li-vesicle tsa neurotransmitter. Ka hona, ts'ebetso ea α2 hangata e thibela ho lokolloa ha noradrenaline - e sebetsang e le mokhoa o mobe oa karabelo ho thibela lets'oao le feteletseng la kutloelo-bohloko. Phello ena e ka fokotsa molumo oa kutloelo-bohloko o bohareng le o ka ntle, ka hona ea theola khatello ea mali.
Meriana ea α2 agonist e kang clonidine kapa methyldopa e sebelisa mokhoa ona ho phekola khatello e phahameng ea mali (le maemong a mang bakeng sa ho kokobetsa kapa matšoao a itseng a ho khaotsa), hobane e thibela tšebetso ea kutloelo-bohloko.
5. Mokhoa oa receptor oa β (β1, β2, β3): Tsela ea Gs - ts'ebetso e eketsehileng ea cAMP le PKA
Li-receptor tsa β1, β2, le β3 hangata li kopana le liprotheine tsa mofuta oa G (tse susumetsang). Ho kengoa tšebetsong ha li-receptor tsa β ho hlohlelletsa adenylate cyclase, ho eketsa tlhahiso ea cAMP, ebe ho kengoa tšebetsong PKA. PKA e ntan'o kenya phosphorylates liprotheine tse fapaneng tse reretsoeng ho latela mofuta oa sele.
a) β1 ka pelong: liphello tse eketsehileng tsa inotropic, chronotropic, le dromotropic
Liseleng tsa pelo le li-node tsa SA/AV, keketseho ea ts'ebetso ea cAMP le PKA e tla:
– E eketsa ho kena ha Ca²⁺ ka likanale tsa calcium tsa mofuta oa L
– E thusa ho lokolla Ca²⁺ ho tsoa ho sarcoplasmic reticulum
– E potlakisa ho nkuwa ha Ca²⁺ e le hore phomolo le yona e potlake (lusitropic)
Sephetho sa ho qetela ke ho eketseha ha ho kokotseha ha pelo (positive inotropic), ho eketseha ha sekgahla sa pelo (positive chronotropic), le ho eketseha ha lebelo la ho tsamaisa mali (positive dromotropic). Ka har'a liphio, β1 e hlohlelletsa lisele tsa juxtaglomerular ho lokolla renin, e leng se kenyang tšebetsong tsamaiso ea RAAS mme hape se susumetsa khatello ea mali le bophahamo ba mokelikeli.
b) β2 mesifa e boreleli: phomolo ka lebaka la ho fokotseha ha ts'ebetso ea MLCK
Hoa thahasellisa hore mesifa e boreleli, keketseho ea cAMP ka β2 e atisa ho baka phomolo. Mokhoa: PKA e etsa phosphorylates le ho thibela MLCK, e leng se fellang ka phosphorylation e fokotsehileng ea myosin le ho fokotseha ha ho honyela. Ka hona, ts'ebetso ea β2 e fella ka:
- Ho ruruha ha bronchial ea tsela ea ho hema
- Ho ruruha ha methapo ea mali ea mesifa ea masapo
– Phomolo ea popelo
Li-agonist tsa β2 tse kang salbutamol li sebelisoa e le li-bronchodilator bakeng sa asthma/COPD.
c) β3 ka har'a lisele tsa mafura le senya
Ka hara lisele tsa mafura, ho kenngwa tshebetsong ha β3 ho eketsa ho bola ha mafura ka tsela ya cAMP/PKA, e kenyang tshebetsong lipase e utlwang dihormone. Ka hara senya, β3 e kgothaletsa ho phomotsa mesifa ya detrusor, e sebediswang ke dithethefatsi tse kang mirabegron bakeng sa senya se sebetsang haholo.
6. Ho felisoa ha lets'oao le ho fokotsa kutloisiso ea li-receptor tsa adrenergic
Karabelo ea adrenergic ha e tsoele pele. Ho na le mekhoa e 'maloa ea ho emisa le ho seta lets'oao bocha:
1. Hydrolysis ea GTP ke karoloana ea α e le hore protheine ea G e se ke ea sebetsa hape.
2. Ho senyeha ha cAMP ke phosphodiesterase (PDE)
3. Ho nkuwa hape ha di-catecholamine le ho sebediswa ha tsona hape: noradrenaline e kgutlisetswa ho di-neuron (ho nkuwa-1) mme e nkuwa ke MAO; di-catecholamine le tsona di nkuwa ke COMT dinama.
4. Ho se sebedisehe ha di-receptor: di-receptor tse atisang ho pepesehela di-agonist di ka phosphorylated ke GRK (G-protein receptor kinase), ebe di tlangwa ho β-arrestin, e leng se bakang phokotseho ya karabelo mme di ka kenngwa ka hare ho disele.
Ketsahalo ena ea ho fokotsa kutloisiso ea 'mele e bohlokoa haholo, mohlala, tšebelisong e feteletseng ea li-agonist tsa β2 tse ka fokotsang katleho ea li-bronchodilator.
7. Kesimpulan
Mokhoa oa tšebetso ea li-receptor tsa adrenergic o itšetlehile ka mofuta oa li-receptor le tsela ea protheine ea G e sebetsang. Li-receptor tsa α1 li sebelisa tsela ea Gq ho eketsa Ca²⁺ le ho susumetsa ho honyela ha mesifa e boreleli, li-receptor tsa α2 li sebelisa G ho fokotsa cAMP le ho thibela ho lokolloa ha neurotransmitter, ha li-receptor tsa β1/β2/β3 li sebelisa G ho eketsa cAMP le ho kenya tšebetsong PKA—e leng se matlafatsang ketso ea ho pompa ka pelong, empa mesifa e itseng e boreleli e hlile e baka phomolo. Taolo ea matšoao ka ho emisa le ho fokotsa kutlo e netefatsa hore karabelo ea kutloelo-bohloko e lula e lekana. Ka kutloisiso ena, re ka hlalosa habonolo liphello tsa lithethefatsi tsa adrenergic le antiadrenergic kalafong ea lefu la pelo le methapo ea mali, mathata a ho hema, urology le maemo a khatello e matla.
