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Drugs Acting on TRPM4 Modulate NMDA Receptors in Hippocampal Neurons
Drugs Acting on TRPM4 Modulate NMDA Receptors in Hippocampal Neurons
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104726
- ISBN
- 9798291502587
- DDC
- 615
- 저자명
- Casby, Jordan.
- 서명/저자
- Drugs Acting on TRPM4 Modulate NMDA Receptors in Hippocampal Neurons
- 발행사항
- [Sl] : University of Minnesota, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 133 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-02, Section: B.
- 주기사항
- Advisor: Thayer, Stanley.
- 학위논문주기
- Thesis (Ph.D.)--University of Minnesota, 2025.
- 초록/해제
- 요약Excitotoxic signaling mediated by N-methyl-D-aspartate receptors (NMDARs) is inhibited by NMDAR/TRPM4 complex inhibitors such as brophenexin (BPN). We used rat hippocampal neurons grown in culture to characterize the pharmacology of BPN and determine its effects on NMDAR and TRPM4 function. NMDA-evoked concentration-dependent increases in the intracellular Ca2+ concentration ([Ca2+]i) were inhibited by 10 µM BPN in a non-competitive manner. In contrast, the TRPM4 inhibitor 4-chloro-2-(2-(naphthalene-1-yloxy) acetamido) benzoic acid (NBA) increased the potency of NMDA (22°C). BPN inhibition of NMDAR-mediated increases in [Ca2+]i was fully reversible and recovered by rapid (30 s) and slow (90 min) processes. The rapid phase of recovery from BPN inhibition was mediated by trafficking through recycling endosomes as indicated by blockade of this phase of recovery by inhibiting endocytosis with high sucrose, preventing endosomal acidification with bafilomycin A1, or inhibiting protein kinase C-mediated exocytosis with Go-6983. The full recovery of NMDAR function observed 90 min after washout of BPN was not affected by these treatments. Immunocytochemistry experiments suggested that BPN did not directly alter NMDAR trafficking but instead changes in surface and internal GluN2B immunoreactivity were likely homeostatic responses to inhibition of NMDAR function by BPN. To determine the effects of BPN on TRPM4 function we examined its effects on NBA-sensitive spontaneous network activity with NMDARs blocked. In the presence of MK-801, 10 µM NBA blocked [Ca2+]i spiking by 74 ± 11 % whereas 10 µM BPN reduced activity by 49 ± 6 %. Overall this study reveals that BPN is a non-competitive, fully reversible inhibitor of NMDAR-mediated Ca2+ influx and that it produced a modest inhibition of TRPM4 function. Functional inhibition of these ion channels likely contributes to the neuroprotective properties of NMDAR/TRPM4 interface inhibitors and the readily reversible nature of this inhibition is consistent with these drugs being well-tolerated.
- 일반주제명
- Pharmacology
- 일반주제명
- Neurosciences
- 일반주제명
- Health sciences
- 키워드
- Calcium
- 키워드
- Hippocampus
- 키워드
- Neuroprotection
- 키워드
- Neurotoxicity
- 기타저자
- University of Minnesota Pharmacology
- 기본자료저록
- Dissertations Abstracts International. 87-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a615
■1001 ▼aCasby, Jordan.
■24510▼aDrugs Acting on TRPM4 Modulate NMDA Receptors in Hippocampal Neurons
■260 ▼a[Sl]▼bUniversity of Minnesota▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a133 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-02, Section: B.
■500 ▼aAdvisor: Thayer, Stanley.
■5021 ▼aThesis (Ph.D.)--University of Minnesota, 2025.
■520 ▼aExcitotoxic signaling mediated by N-methyl-D-aspartate receptors (NMDARs) is inhibited by NMDAR/TRPM4 complex inhibitors such as brophenexin (BPN). We used rat hippocampal neurons grown in culture to characterize the pharmacology of BPN and determine its effects on NMDAR and TRPM4 function. NMDA-evoked concentration-dependent increases in the intracellular Ca2+ concentration ([Ca2+]i) were inhibited by 10 µM BPN in a non-competitive manner. In contrast, the TRPM4 inhibitor 4-chloro-2-(2-(naphthalene-1-yloxy) acetamido) benzoic acid (NBA) increased the potency of NMDA (22°C). BPN inhibition of NMDAR-mediated increases in [Ca2+]i was fully reversible and recovered by rapid (30 s) and slow (90 min) processes. The rapid phase of recovery from BPN inhibition was mediated by trafficking through recycling endosomes as indicated by blockade of this phase of recovery by inhibiting endocytosis with high sucrose, preventing endosomal acidification with bafilomycin A1, or inhibiting protein kinase C-mediated exocytosis with Go-6983. The full recovery of NMDAR function observed 90 min after washout of BPN was not affected by these treatments. Immunocytochemistry experiments suggested that BPN did not directly alter NMDAR trafficking but instead changes in surface and internal GluN2B immunoreactivity were likely homeostatic responses to inhibition of NMDAR function by BPN. To determine the effects of BPN on TRPM4 function we examined its effects on NBA-sensitive spontaneous network activity with NMDARs blocked. In the presence of MK-801, 10 µM NBA blocked [Ca2+]i spiking by 74 ± 11 % whereas 10 µM BPN reduced activity by 49 ± 6 %. Overall this study reveals that BPN is a non-competitive, fully reversible inhibitor of NMDAR-mediated Ca2+ influx and that it produced a modest inhibition of TRPM4 function. Functional inhibition of these ion channels likely contributes to the neuroprotective properties of NMDAR/TRPM4 interface inhibitors and the readily reversible nature of this inhibition is consistent with these drugs being well-tolerated.
■590 ▼aSchool code: 0130.
■650 4▼aPharmacology
■650 4▼aNeurosciences
■650 4▼aHealth sciences
■653 ▼aCalcium
■653 ▼aHippocampus
■653 ▼aNeuroprotection
■653 ▼aNeurotoxicity
■690 ▼a0419
■690 ▼a0566
■690 ▼a0317
■71020▼aUniversity of Minnesota▼bPharmacology.
■7730 ▼tDissertations Abstracts International▼g87-02B.
■790 ▼a0130
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358608▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
