Cellular and molecular pharmacology of the lipid-sensitive channel TMEM16A/Anoctamin1
TMEM16A Ca2+-activated Cl- channels (CaCC) control vital functions including arterial smooth muscle tone and blood flow. The TMEM16A has a pore with regions surrounding plasmalemmal lipids, an arrangement where lipids can directly influence the ion permeation and gating of the channel. Here, it is h...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Thesis |
| Language: | English |
| Published: |
2022
|
| _version_ | 1797107670753214464 |
|---|---|
| author | Scofano, LF |
| author2 | Tammaro, P |
| author_facet | Tammaro, P Scofano, LF |
| author_sort | Scofano, LF |
| collection | OXFORD |
| description | TMEM16A Ca2+-activated Cl- channels (CaCC) control vital functions including arterial smooth muscle tone and blood flow. The TMEM16A has a pore with regions surrounding plasmalemmal lipids, an arrangement where lipids can directly influence the ion permeation and gating of the channel. Here, it is hypothesised that TMEM16A channel may serve as a lipid sensor and couple changes in lipid metabolism to changes in cell electrical activity. It is also argued that TMEM16A channels may be indirectly modulated by the lysosome and in particular by the lysosomal lipid transporter Niemann-Pick type C 1 (NPC1) protein, given the key involvement of this organelle in the control of plasmalemmal lipid composition. Thus, it is suggested that changes in the plasmalemmal composition driven by lysosomes, can modulate the plasma membrane-residing TMEM16A channel, impacting vascular function. Indeed loss-of-function mutations in NPC1 leads to Niemann-Pick disease Type C (NPC), a neurodegenerative disorder with a range of systemic alterations, including vascular. Here, I explore the capacity of the NPC1 to control TMEM16A function, and examine the consequence of this modulation on the tone of isolated arteries, which abundantly express TMEM16A. Key results include: (i) TMEM16A currents were enhanced during NPC1 inhibition; (ii) depletion of plasmalemmal phosphatidylinositol 4,5-biphosphate (PIP2) prevented this activation; (iii) plasmalemmal PIP2 distribution was increased during NPC1 inhibition; (iv) aortic rings and cerebral capillaries obtained from Npc1 null mice showed enhanced contractility; (v) β-cyclodextrin, a drug currently studied for treating NPC disease, prevented TMEM16A activation and aortic contractility in samples obtained from Npc1 null mice. These results indicate that TMEM16A activity is modulated by NPC1. This regulation affects the tone of arteries. PIP2-dependent changes in TMEM16A activity may be the basis of vascular overactivity associated with NPC disease. |
| first_indexed | 2024-03-07T07:19:09Z |
| format | Thesis |
| id | oxford-uuid:f5354ad3-20fc-4e8a-9735-137d6539bfa6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:19:09Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:f5354ad3-20fc-4e8a-9735-137d6539bfa62022-09-09T16:17:53ZCellular and molecular pharmacology of the lipid-sensitive channel TMEM16A/Anoctamin1Thesishttp://purl.org/coar/resource_type/c_db06uuid:f5354ad3-20fc-4e8a-9735-137d6539bfa6EnglishHyrax Deposit2022Scofano, LFTammaro, PPlatt, FTMEM16A Ca2+-activated Cl- channels (CaCC) control vital functions including arterial smooth muscle tone and blood flow. The TMEM16A has a pore with regions surrounding plasmalemmal lipids, an arrangement where lipids can directly influence the ion permeation and gating of the channel. Here, it is hypothesised that TMEM16A channel may serve as a lipid sensor and couple changes in lipid metabolism to changes in cell electrical activity. It is also argued that TMEM16A channels may be indirectly modulated by the lysosome and in particular by the lysosomal lipid transporter Niemann-Pick type C 1 (NPC1) protein, given the key involvement of this organelle in the control of plasmalemmal lipid composition. Thus, it is suggested that changes in the plasmalemmal composition driven by lysosomes, can modulate the plasma membrane-residing TMEM16A channel, impacting vascular function. Indeed loss-of-function mutations in NPC1 leads to Niemann-Pick disease Type C (NPC), a neurodegenerative disorder with a range of systemic alterations, including vascular. Here, I explore the capacity of the NPC1 to control TMEM16A function, and examine the consequence of this modulation on the tone of isolated arteries, which abundantly express TMEM16A. Key results include: (i) TMEM16A currents were enhanced during NPC1 inhibition; (ii) depletion of plasmalemmal phosphatidylinositol 4,5-biphosphate (PIP2) prevented this activation; (iii) plasmalemmal PIP2 distribution was increased during NPC1 inhibition; (iv) aortic rings and cerebral capillaries obtained from Npc1 null mice showed enhanced contractility; (v) β-cyclodextrin, a drug currently studied for treating NPC disease, prevented TMEM16A activation and aortic contractility in samples obtained from Npc1 null mice. These results indicate that TMEM16A activity is modulated by NPC1. This regulation affects the tone of arteries. PIP2-dependent changes in TMEM16A activity may be the basis of vascular overactivity associated with NPC disease. |
| spellingShingle | Scofano, LF Cellular and molecular pharmacology of the lipid-sensitive channel TMEM16A/Anoctamin1 |
| title | Cellular and molecular pharmacology of the lipid-sensitive channel TMEM16A/Anoctamin1 |
| title_full | Cellular and molecular pharmacology of the lipid-sensitive channel TMEM16A/Anoctamin1 |
| title_fullStr | Cellular and molecular pharmacology of the lipid-sensitive channel TMEM16A/Anoctamin1 |
| title_full_unstemmed | Cellular and molecular pharmacology of the lipid-sensitive channel TMEM16A/Anoctamin1 |
| title_short | Cellular and molecular pharmacology of the lipid-sensitive channel TMEM16A/Anoctamin1 |
| title_sort | cellular and molecular pharmacology of the lipid sensitive channel tmem16a anoctamin1 |
| work_keys_str_mv | AT scofanolf cellularandmolecularpharmacologyofthelipidsensitivechanneltmem16aanoctamin1 |