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The Role of G Protein-Coupled Receptor Kinases in Opioid Receptor Functional Selectivity
The Role of G Protein-Coupled Receptor Kinases in Opioid Receptor Functional Selectivity
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151353
- ISBN
- 9798382812304
- DDC
- 574
- 저자명
- Li, Joy.
- 서명/저자
- The Role of G Protein-Coupled Receptor Kinases in Opioid Receptor Functional Selectivity
- 발행사항
- [Sl] : University of California, San Francisco, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 123 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-12, Section: B.
- 주기사항
- Advisor: Narlikar, Geeta.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2024.
- 초록/해제
- 요약G protein-coupled receptor (GPCR) signal transduction is a fundamental building block of cell biology, yet how different ligands such as peptide agonists and small molecules can act at the same receptor to produce different functional outcomes is not fully appreciated. A proliferation of biochemical, biophysical, and pharmacological studies led to an abundance of receptor active-state structures and candidate molecules selective for desired outcomes while avoiding side effects. With preponderance of data, however, also came contradictions and challenges in interpretations. This thesis returns to the basic step of ligand-receptor-effector interaction, and explores two fundamental questions: 1) can different agonists selectively couple the receptor to different cytoplasmic proteins in intact cells? and 2) in the agonist-selective receptor endocytosis pathway, how do GPCR kinases (GRKs) recognize different agonist-bound receptors? Using two engineered protein biosensors as discreet intracellular proteins, two agonists showed distinctly different profiles in recruiting the protein biosensors. This result provides a proof of concept of a potential answer to the first question, that in a 'clean' cellular environment without native signaling interference, agonists can indeed engage two different biosensors with selective preferences. Similarly for the second question, using an engineered GRK-free cellular background, a single GRK subtype was shown to produce agonist-selective functional outcome of receptor internalization. This GRK was also recruited to the receptor in an agonist-selective manner, supporting the hypothesis that selective functional outcomes begin upstream at selective receptor-GRK interactions. Furthermore, a single domain was shown to be the key selectivity determinant for GRK recruitment to the receptor and internalization function.
- 일반주제명
- Cellular biology
- 일반주제명
- Molecular biology
- 일반주제명
- Biochemistry
- 키워드
- GPCR kinases
- 키워드
- Opioid receptors
- 키워드
- Small molecules
- 기타저자
- University of California, San Francisco Biochemistry and Molecular Biology
- 기본자료저록
- Dissertations Abstracts International. 85-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798382812304
■035 ▼a(MiAaPQ)AAI31243454
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aLi, Joy.▼0(orcid)0009-0003-7943-3596
■24510▼aThe Role of G Protein-Coupled Receptor Kinases in Opioid Receptor Functional Selectivity
■260 ▼a[Sl]▼bUniversity of California, San Francisco▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a123 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-12, Section: B.
■500 ▼aAdvisor: Narlikar, Geeta.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2024.
■520 ▼aG protein-coupled receptor (GPCR) signal transduction is a fundamental building block of cell biology, yet how different ligands such as peptide agonists and small molecules can act at the same receptor to produce different functional outcomes is not fully appreciated. A proliferation of biochemical, biophysical, and pharmacological studies led to an abundance of receptor active-state structures and candidate molecules selective for desired outcomes while avoiding side effects. With preponderance of data, however, also came contradictions and challenges in interpretations. This thesis returns to the basic step of ligand-receptor-effector interaction, and explores two fundamental questions: 1) can different agonists selectively couple the receptor to different cytoplasmic proteins in intact cells? and 2) in the agonist-selective receptor endocytosis pathway, how do GPCR kinases (GRKs) recognize different agonist-bound receptors? Using two engineered protein biosensors as discreet intracellular proteins, two agonists showed distinctly different profiles in recruiting the protein biosensors. This result provides a proof of concept of a potential answer to the first question, that in a 'clean' cellular environment without native signaling interference, agonists can indeed engage two different biosensors with selective preferences. Similarly for the second question, using an engineered GRK-free cellular background, a single GRK subtype was shown to produce agonist-selective functional outcome of receptor internalization. This GRK was also recruited to the receptor in an agonist-selective manner, supporting the hypothesis that selective functional outcomes begin upstream at selective receptor-GRK interactions. Furthermore, a single domain was shown to be the key selectivity determinant for GRK recruitment to the receptor and internalization function.
■590 ▼aSchool code: 0034.
■650 4▼aCellular biology
■650 4▼aMolecular biology
■650 4▼aBiochemistry
■653 ▼aAgonist selectivity
■653 ▼aG protein-coupled receptor
■653 ▼aGPCR kinases
■653 ▼aOpioid receptors
■653 ▼aSmall molecules
■690 ▼a0379
■690 ▼a0307
■690 ▼a0487
■71020▼aUniversity of California, San Francisco▼bBiochemistry and Molecular Biology.
■7730 ▼tDissertations Abstracts International▼g85-12B.
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17161416▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
