The role of TASK-1 potassium channels in pulmonary artery smooth muscle
Lead Research Organisation:
University of Manchester
Department Name: Life Sciences
Abstract
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Technical Summary
This study will investigate the functional role of the two-pore domain K channel, TASK-1, in pulmonary arteries, using small interfering RNA to induce gene silencing in vitro. Of particular interest is the role of TASK-1 in hypoxic pulmonary vasoconstriction. Patch-clamp techniques will be used to compare the properties of the resting K+ conductance and resting membrane potential in isolated smooth muscle cells before and after TASK-1 silencing. The role of TASK-1 in the regulation of intracellular CA2+ concentration will be studied in isolated cells and intact vessels using fluorescence imaging techniques. Small vessel myography will be used to investigate how TASK-1 expression influences pulmonary vascular tone.
People |
ORCID iD |
| Alison Gurney (Principal Investigator) |
Publications
Gurney A
(2009)
Two-pore potassium channels in the cardiovascular system.
in European biophysics journal : EBJ
Joshi S
(2009)
KCNQ modulators reveal a key role for KCNQ potassium channels in regulating the tone of rat pulmonary artery smooth muscle.
in The Journal of pharmacology and experimental therapeutics
Manoury B
(2009)
Organ culture mimics the effects of hypoxia on membrane potential, K(+) channels and vessel tone in pulmonary artery.
in British journal of pharmacology
Manoury B
(2011)
Contractile and electrophysiological properties of pulmonary artery smooth muscle are not altered in TASK-1 knockout mice.
in The Journal of physiology
| Description | A clear link was established between expression of the TASK-1 (KCNK3) gene and the constriction of pulmonary arteries. We showed that this gene codes for a protein that forms an ion channel in the membrane of muscle cells surrounding pulmonary arteries. When the channel opens, potassium ions leave the cell and hyper-polarise the membrane, causing the muscle cell to relax and the artery to dilate. To aid in establishing this mechanism, methods were developed and optimised for (1) maintaining pulmonary arteries in culture, with minimal change in ion channel function, muscle contraction and pharmacology, and (2) silencing channel activity in intact artery preparations using small interfering RNA. We also established that the mouse is not a suitable model for studying TASK-1 channels in pulmonary arteries, because mouse arteries do not express the functional channel. |
| Exploitation Route | Studies of the TASK-1 channel in animal models of pulmonary vascular disease would help to elucidate the role of the channel in the development of disease and allow TASK-1 channel modulating drugs to be tested for their therapeutic potential. |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| Description | Since this work was completed, a separate group has established that mutations in the KCNK3 (TASK-1) gene give rise to pulmonary hypertension in affected families. Our studies, which first demonstrated the key role of the channel in pulmonary arteries were fundamental to that discovery. |
| First Year Of Impact | 2013 |
| Sector | Education,Pharmaceuticals and Medical Biotechnology |
| Description | Collaboration with pharmaceutical company to investigate drug targets in pulmonary disease |
| Organisation | Ono Pharmaceutical |
| Country | Japan |
| Sector | Private |
| PI Contribution | Preclinical research: Evaluation of specific ion channel targets for treating pulmonary disease |
| Collaborator Contribution | Contributions were primarily financial Regular discussions about the project, including feedback on the areas considered of most or least value to the company |
| Impact | Reports to the company Publications in progress |
| Start Year | 2011 |