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6.8:

G-๋‹จ๋ฐฑ์งˆ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด

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G-protein Coupled Receptors

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– [๊ฐ•์‚ฌ] G ๋‹จ๋ฐฑ์งˆ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด, ๋˜๋Š” GPCR์€ํ•„์ˆ˜์ ์ธ ๋ง‰ ๋‹จ๋ฐฑ์งˆ์˜ ๋˜ ๋‹ค๋ฅธ ์œ ํ˜•์ž…๋‹ˆ๋‹ค๋ง‰ ๋ฐ–์œผ๋กœ ํŠ€์–ด๋‚˜์˜จ ์„ธํฌ ์™ธ๊ด€ ๋ถ€๋ถ„์€๋‹ค์–‘ํ•œ ํ™”ํ•ฉ๋ฌผ์— ๋Œ€ํ•œ ๋ฆฌ๊ฐ„๋“œ ๊ฒฐํ•ฉ ๋ถ€์œ„๊ฐ€ ํฌํ•จ๋ผ์žˆ์Šต๋‹ˆ๋‹ค์„ธํฌ ๋‚ด ๋ถ€๋ถ„์€ G ๋‹จ๋ฐฑ์งˆ๊ณผ ๊ฒฐํ•ฉ๋˜๋Š”๋ฐ์„ธ ๊ฐ€์ง€์˜ ๋‹ค๋ฅธ ํ•˜์œ„ ๋‹จ์œ„๋กœ ๊ตฌ์„ฑ๋˜๋Š”๋ฐ์•ŒํŒŒ, ๋ฒ ํƒ€ ๋ฐ ๊ฐ๋งˆ์ž…๋‹ˆ๋‹ค๋ฆฌ๊ฐ„๋“œ๊ฐ€ ๊ฒฐํ•ฉํ•˜๋ฉด ์ˆ˜์šฉ์ฒด๊ฐ€ ๋ณ€ํ˜•๋˜๊ณ ๊ตฌ์•„๋…ธ์‹ ์ด์ธ์‚ฐ, ํ˜น์€ GDP๊ฐ€๋ฐฉ์ถœ๋  ์•ŒํŒŒ ์†Œ๋‹จ์œ„์— ์˜ํ•ด ๋ฌถ์ด๋ฉฐ๊ตฌ์•„๋…ธ์‹ 3์ธ์‚ฐ์œผ๋กœ ๋Œ€์ฒด๋˜๋Š”๋ฐ์ด๋Š” ๋˜ํ•œ GTP ๋ถ„์ž์ž…๋‹ˆ๋‹ค์ด ๋‘ ๊ฐœ๋Š” ๋ฒ ํƒ€ ๋ฐ ๊ฐ๋งˆ์˜ ์„œ๋ธŒ ์œ ๋‹›์—์„œ ๋ถ„๋ฆฌ๋ฉ๋‹ˆ๋‹ค์ด์ œ, ์–‘ ์ชฝ์˜ ํŒŒํŽธ ๋ชจ์Œ์€ ์ž์œ ๋กญ๊ฒŒ์„ธํฌ์งˆ์„ ๋Œ์•„ ๋‹ค๋‹ˆ๋ฉฐ ์ƒํ˜ธ ์ž‘์šฉ์„๋‹ค๋ฅธ ์ดํŽ™ํ„ฐ๋‹จ๋ฐฑ์งˆ๊ณผ ์ด๋ฃจ๋Š”๋ฐ์ด๋“ค์€ ์ผ๋ จ์˜ ์„ธํฌ ๋‚ด ์‹ ํ˜ธ ์บ์Šค์บ์ด๋“œ๋ฅผ ํ™œ์„ฑ์‹œํ‚ค๋ฉฐ์ด๋“ค์€ ์‹ ํ˜ธ๋ฅผ ์ง€์‹œํ•˜๊ณ  ์ฆํญ์‹œํ‚ค๋Š” ์—ญํ• ์„ ํ•ฉ๋‹ˆ๋‹ค์ด ๊ณผ์ •์˜ ์ข…๊ฒฐ์€ GTP๊ฐ€ GDP๋กœ ๊ฐ€์ˆ˜ ๋ถ„ํ•ด๋˜๊ณ G ๋‹จ๋ฐฑ์งˆ ์„œ๋ธŒ ์œ ๋‹›์€ ์žฌ์กฐํ•ฉ์œผ๋กœ๋‹ค์‹œ ๋น„ํ™œ์„ฑ ํ˜•ํƒœ๋กœ ๋Œ์•„๊ฐ€๋ฉฐ ๋งˆ๋ฌด๋ฆฌ๋˜๋ฉฐGPCR์€ ์ƒˆ๋กœ์šด ์‹ ํ˜ธ๋ฅผ ๋ฐ›์„ ์ค€๋น„๊ฐ€ ๋ฉ๋‹ˆ๋‹ค

6.8:

G-๋‹จ๋ฐฑ์งˆ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด

G-๋‹จ๋ฐฑ์งˆ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด(G-protein coupled receptor)๋Š” ์„ธํฌ์˜ ๋ณ€ํ™”์— โ€‹โ€‹๊ฐ„์ ‘์ ์œผ๋กœ ์˜ํ–ฅ์„ ๋ฏธ์น˜๋Š” ๋ฆฌ๊ฐ„๋“œ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด(ligand binding receptor)์ž…๋‹ˆ๋‹ค. ์‹ค์ œ ์ˆ˜์šฉ์ฒด๋Š” ์„ธํฌ๋ง‰์„ 7๋ฒˆ ๊ฐ€๋กœ์ง€๋ฅด๋Š” ๋‹จ์ผ ํด๋ฆฌํŽฉํƒ€์ด๋“œ(polypeptide)๋กœ ์„ธํฌ ์•ˆํŒŽ์— ๊ณ ๋ฆฌ๋ฅผ ํ˜•์„ฑํ•ฉ๋‹ˆ๋‹ค. ์„ธํฌ ์™ธ ๊ณ ๋ฆฌ๋Š” ์‹ ๊ฒฝ์ „๋‹ฌ๋ฌผ์งˆ์ด๋‚˜ ํ˜ธ๋ฅด๋ชฌ๊ณผ ๊ฒฐํ•ฉํ•˜๋Š” ๋ฆฌ๊ฐ„๋“œ ํŠน์ • ์ฃผ๋จธ๋‹ˆ(ligand specific pocket)๋ฅผ ํ˜•์„ฑํ•ฉ๋‹ˆ๋‹ค. ์„ธํฌ ๋‚ด ๊ณ ๋ฆฌ๋Š” G-๋‹จ๋ฐฑ์งˆ์„ ๋ถ™๋“ญ๋‹ˆ๋‹ค.

G-๋‹จ๋ฐฑ์งˆ(์ฆ‰, ๊ตฌ์•„๋‹Œ ๋‰ดํด๋ ˆ์˜คํƒ€์ด๋“œ ๊ฒฐํ•ฉ ๋‹จ๋ฐฑ์งˆ(guanine nucleotide-binding protein))์€ ํฐ ์ด์ข… ์‚ผ๋Ÿ‰ ๋ณตํ•ฉ์ฒด(heterotrimeric complex)์ž…๋‹ˆ๋‹ค. ์ด ๋‹จ๋ฐฑ์งˆ์˜ 3๊ฐœ์˜ ๋‹จ์œ„์ฒด(subunit)๋Š” ์•ŒํŒŒ(α), ๋ฒ ํƒ€(β), ๊ฐ๋งˆ(γ)๋กœ ๋ถ„๋ฅ˜๋ฉ๋‹ˆ๋‹ค. ์ˆ˜์šฉ์ฒด๊ฐ€ ๊ฒฐํ•ฉํ•˜์ง€ ์•Š์•˜๊ฑฐ๋‚˜ ์‰ฌ๊ณ  ์žˆ์œผ๋ฉด ์•ŒํŒŒ ๋‹จ์œ„์ฒด๋Š” ๊ตฌ์•„๋…ธ์‹ ์ด์ธ์‚ฐ(guanosine diphosphate, ์ค„์—ฌ์„œ GDP) ๋ถ„์ž์— ๊ฒฐํ•ฉํ•˜๋ฉฐ, (์•ŒํŒŒ ๋‹จ์œ„์ฒด๋ฅผ ํฌํ•จํ•œ) ์„ธ ๋‹จ์œ„์ฒด ๋ชจ๋‘ ์ˆ˜์šฉ์ฒด์—๋„ ๊ฒฐํ•ฉํ•ฉ๋‹ˆ๋‹ค.

๋ฆฌ๊ฐ„๋“œ๊ฐ€ ์ˆ˜์šฉ์ฒด์— ๊ฒฐํ•ฉํ•˜๋ฉด ์•ŒํŒŒ ๋‹จ์œ„์ฒด๋Š” GDP๋ฅผ ๋ฐฉ์ถœํ•˜๊ณ  ๊ตฌ์•„๋…ธ์‹ ์‚ผ์ธ์‚ฐ(guanosine triphosphate, ์ค„์—ฌ์„œ GTP) ๋ถ„์ž์— ๊ฒฐํ•ฉํ•ฉ๋‹ˆ๋‹ค. ์ด ์ž‘์šฉ์€ α-GTP ๋ณตํ•ฉ์ฒด์™€ β-&gamma ๋ณตํ•ฉ์ฒด๋ฅผ ๋ฐฉ์ถœํ•ฉ๋‹ˆ๋‹ค. α-GTP๋Š” ๊ณ ๋ฆฌํ˜• ์•„๋ฐ๋…ธ์‹ ์ผ์ธ์‚ฐ(cyclic adenosine monophosphate, ์ค„์—ฌ์„œ cAMP) ๊ฐ™์€ 2์ฐจ ์ „๋‹ฌ์ž ๊ฒฝ๋กœ๋ฅผ ํ™œ์„ฑํ™”ํ•˜๊ธฐ ์œ„ํ•ด ๋ง‰์„ ๋”ฐ๋ผ ์›€์ง์ผ ์ˆ˜ ์žˆ์ง€๋งŒ, ๋™์‹œ์— ๋‹ค๋ฅธ ์œ ํ˜•์˜ ์•ŒํŒŒ ๋‹จ์œ„์ฒด ์ค‘ ์ผ๋ถ€์—๊ฒŒ ์–ต์ œํ•˜๋Š” ํž˜์ด ์žˆ์–ด cAMP๋ฅผ ๋น„ํ™œ์„ฑํ™”ํ•  ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค.

β-γ ๋ณตํ•ฉ์ฒด๋Š” ์นผ๋ฅจ(K+)์„ ์„ธํฌ ์™ธ ๊ณต๊ฐ„์œผ๋กœ ๋ฐฉ์ถœํ•˜๋Š” ์นผ๋ฅจ ์ด์˜จ ์ฑ„๋„(potassium ion channel)๊ณผ ์ƒํ˜ธ์ž‘์šฉํ•˜์—ฌ ์„ธํฌ๋ง‰์˜ ๊ณผ๋ถ„๊ทน(hyperpolarization)์„ ์ผ์œผํ‚ฌ ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค. ์ด ์œ ํ˜•์˜ ๋ฆฌ๊ฐ„๋“œ ๊ฐœํ ์ด์˜จ ์ฑ„๋„(ligand-gated ion channel)์€ G-๋‹จ๋ฐฑ์งˆ ์˜์กด์„ฑ ๋‚ด๋ถ€์ •๋ฅ˜ ์นผ๋ฅจ ์ฑ„๋„(G-protein coupled inwardly rectifying potassium channel), ์ค„์—ฌ์„œ GIRK์ด๋ผ๊ณ  ํ•ฉ๋‹ˆ๋‹ค.

๋ฆฌ๊ฐ„๋“œ๋Š” ์ˆ˜์šฉ์ฒด์— ์˜๊ตฌ์ ์œผ๋กœ ๊ฒฐํ•ฉํ•˜์ง€ ์•Š์Šต๋‹ˆ๋‹ค. ๋ฆฌ๊ฐ„๋“œ๊ฐ€ ์ˆ˜์šฉ์ฒด๋ฅผ ๋ฒ—์–ด๋‚˜๋ฉด G-๋‹จ๋ฐฑ์งˆ ๋‹จ์œ„๊ฐ€ ์žฌ๊ฒฐํ•ฉํ•˜๊ณ  ์žฌ๋ถ€์ฐฉํ•  ์ˆ˜ ์žˆ๊ฒŒ ๋ฉ๋‹ˆ๋‹ค. ๊ทธ๋Ÿฌ๋‚˜ G-๋‹จ๋ฐฑ์งˆ ๋‹จ์œ„๊ฐ€ ์žฌ๊ฒฐํ•ฉ/์žฌ๋ถ€์ฐฉํ•˜๋ ค๋ฉด ์ธ๊ทผ ํšจ์†Œ๊ฐ€ ์•ŒํŒŒ ๋‹จ์œ„์ฒด์— ๊ฒฐํ•ฉํ•œ GTP๋ฅผ ๋‹ค์‹œ GDP๋กœ ๊ฐ€์ˆ˜๋ถ„ํ•ด(hydrolysis)ํ•ด์•ผ ํ•ฉ๋‹ˆ๋‹ค. ์ด๊ฒƒ์ด ์ด๋ฃจ์–ด์ง€๋ฉด β-γ ๋ณตํ•ฉ์ฒด์™€ GDP-α ๋ณตํ•ฉ์ฒด๊ฐ€ ์žฌ์กฐ๋ฆฝ๋˜๊ณ  ์ „์ฒด G-๋‹จ๋ฐฑ์งˆ์ด ์ˆ˜์šฉ์ฒด ์˜์—ญ์— ๋‹ค์‹œ ๋ถ€์ฐฉํ•ฉ๋‹ˆ๋‹ค.

์ผ๋ฐ˜์ ์ธ G-๋‹จ๋ฐฑ์งˆ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด๋Š” ๊ณจ๊ฒฉ๊ทผ์—์„œ ๋ฐœ๊ฒฌ๋˜๋Š” ๋ฌด์Šค์นด๋ฆฐ์„ฑ ์•„์„ธํ‹ธ์ฝœ๋ฆฐ ์ˆ˜์šฉ์ฒด(muscarinic acetylcholine receptor), ์‹ฌ์žฅ์˜ ๋ฒ ํƒ€-1 ์•„๋“œ๋ ˆ๋‚ ๋ฆฐ ์ˆ˜์šฉ์ฒด(Beta-1 adrenergic receptor), ํ‰ํ™œ๊ทผ ์„ธํฌ์— ์žˆ๋Š” ๋ฐ”์†Œํ”„๋ ˆ์‹  ์ˆ˜์šฉ์ฒด(vasopressin receptor)์ž…๋‹ˆ๋‹ค. ํ›„๊ฐ ์ˆ˜์šฉ์ฒด(olfactory receptor)์™€ ์ผ๋ถ€ ๋ฏธ๊ฐ ์ˆ˜์šฉ์ฒด(taste receptor)์™€ ๊ฐ™์€ ๊ฐ๊ฐ๊ณ„ ๋‚ด ์ˆ˜์šฉ์ฒด์— ๊ฒฐํ•ฉํ•˜๋Š” ๋ฆฌ๊ฐ„๋“œ๋Š” ํ™˜๊ฒฝ์—์„œ ์˜จ ๋ถ„์ž์ž…๋‹ˆ๋‹ค. ์˜ˆ๋ฅผ ๋“ค์–ด ์ž๋‹น(sucrose) ๋ถ„์ž๋Š” G-๋‹จ๋ฐฑ์งˆ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด์— ๊ฒฐํ•ฉํ•ด ๋‹จ๋ง›์ด ์ธ์‹๋˜๊ฒŒ ๋งŒ๋“ญ๋‹ˆ๋‹ค.

G-๋‹จ๋ฐฑ์งˆ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด์˜ ๋ณ€ํ˜•์€ ์šฐ์šธ์ฆ ๋“ฑ ๊ธฐ๋ถ„ ์žฅ์• ์— ํฐ ์—ญํ• ์„ ํ•  ์ˆ˜ ์žˆ์Šต๋‹ˆ๋‹ค. ์„ธ๋กœํ† ๋‹Œ(serotonin)์€ G-๋‹จ๋ฐฑ์งˆ ๊ฒฐํ•ฉ ์ˆ˜์šฉ์ฒด์ธ 5HT1A ์ˆ˜์šฉ์ฒด(5HT1A receptor)์˜ ๋ฆฌ๊ฐ„๋“œ์ž…๋‹ˆ๋‹ค. ์šฐ์šธ์ฆ์ด ์žˆ์„ ๋•Œ ๋ฆฌ๊ฐ„๋“œ์™€ ์ˆ˜์šฉ์ฒด ์‚ฌ์ด์˜ ์ƒํ˜ธ์ž‘์šฉ์ด ๋ณ€ํ™”ํ•œ๋‹ค๊ณ  ์ œ์•ˆ๋œ ์ ์ด ์žˆ์Šต๋‹ˆ๋‹ค. ์ด๋•Œ ๋ฆฌ๊ฐ„๋“œ๊ฐ€ ์ถฉ๋ถ„ํžˆ ๊ธธ๊ฒŒ ๊ฒฐํ•ฉํ•˜์ง€ ์•Š๊ฑฐ๋‚˜ ์ˆ˜์šฉ์ฒด๊ฐ€ ์™„์ „ํžˆ ์‘๋‹ตํ•˜์ง€ ์•Š์•„ ์„ธ๋กœํ† ๋‹Œ์ž‘๋™์„ฑ ์‹ ํ˜ธ์ „๋‹ฌ(serotonergic signaling)์ด ์ €ํ•˜๋˜๊ณ  ์šฐ์šธ์ฆ์œผ๋กœ ๋‚˜ํƒ€๋‚ฉ๋‹ˆ๋‹ค.

Suggested Reading

Gurevich, Vsevolod V., and Eugenia V. Gurevich. “Molecular Mechanisms of GPCR Signaling: A Structural Perspective.” International Journal of Molecular Sciences 18, no. 12 (November 24, 2017). [Source]

Katritch, Vsevolod, Vadim Cherezov, and Raymond C. Stevens. “Structure-Function of the G-Protein-Coupled Receptor Superfamily.” Annual Review of Pharmacology and Toxicology 53 (January 6, 2013): 531–56. [Source]

Bar-Shavit, Rachel, Myriam Maoz, Arun Kancharla, Jeetendra Kumar Nag, Daniel Agranovich, Sorina Grisaru-Granovsky, and Beatrice Uziely. “G Protein-Coupled Receptors in Cancer.” International Journal of Molecular Sciences 17, no. 8 (August 12, 2016). [Source]