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Exploring a role for heteromerization in GPCR signalling specificity

期刊

BIOCHEMICAL JOURNAL
卷 433, 期 -, 页码 11-18

出版社

PORTLAND PRESS LTD
DOI: 10.1042/BJ20100458

关键词

adrenergic receptor; beta-arrestin; G-protein-coupled receptor (GPCR); heteromerization; mitogen-activated protein kinase (MAPK); signal specificity

资金

  1. National Institutes of Health [DA08863, DA01952, GM071558, AA017067]
  2. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P50GM071558] Funding Source: NIH RePORTER
  3. NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [P20AA017067] Funding Source: NIH RePORTER
  4. NATIONAL INSTITUTE ON DRUG ABUSE [K05DA019521, R01DA008863, R37DA008863, R56DA008863] Funding Source: NIH RePORTER

向作者/读者索取更多资源

The critical involvement of GPCRs (G-protein-coupled receptors) in nearly all physiological processes, and the presence of these receptors at the interface between the extracellular and the intracellular milieu, has positioned these receptors as pivotal therapeutic targets. Although a large number of drugs targeting GPCRs are currently available, significant efforts have been directed towards understanding receptor properties, with the goal of identifying and designing improved receptor ligands. Recent advances in GPCR pharmacology have demonstrated that different ligands binding to the same receptor can activate discrete sets of downstream effectors, a phenomenon known as ligand-directed signal specificity', which is currently being explored for drug development due to its potential therapeutic advantage. Emerging studies suggest that GPCR responses can also be modulated by contextual factors, such as interactions with other GPCRs. Association between different GPCR types leads to the formation of complexes, or GPCR heteromers, with distinct and unique signalling properties. Some of these heteromers activate discrete sets of signalling effectors upon activation by the same ligand, a phenomenon termed 'heteromer-directed signalling specificity'. This has been shown to be involved in the physiological role of receptors and, in some cases, in disease-specific dysregulation of a receptor effect. Hence targeting GPCR heteromers constitutes an emerging strategy to select receptor-specific responses and is likely to be useful in achieving specific beneficial therapeutic effects.

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