Exploring the TMEM206 proton-gated chloride channel as a new therapeutic target in ischaemic-mediated capillary disfunction
Lead supervisors: Prof. Paolo Tammaro,
Co-supervisor: Prof. Phil Biggin, Prof. Ming Lei
Commercial partner: Novo Nordisk Research Centre Oxford (NNRCO)
Mammalian cells respond to alterations in extracellular pH (pHe) with mechanisms that are aimed at re-establishing cellular homeostasis. Thus, mammalian cells present specific pH sensors to detect and respond to alterations in pHe. The H+-activated chloride channel (PAC), encoded by the TMEM206 (PACC1) gene, constitutes one of these mechanisms. PAC controls cellular function, such as neuronal cells swelling, in response to ischaemia-induced acidification and modulation of intraluminal H+ and Cl- homeostasis in lysosomes (Front Biosci 2023;28(1):11). PAC is also involved in diseases such as (i) grey matter damage following ischaemic stroke (Science 2019;364(6438):395-9) and (ii) cancer cell hyperplasia and metastasis (Front Biosci 2023;28(1):11). Transcriptome studies show that PAC is expressed in pericytes, contractile cells that surround capillaries, where PAC activation may be responsible for deleterious capillary constriction during ischaemic stroke or myocardial infarction.
PAC is an homotrimer with each subunit comprising of two transmembrane-domains (TMD) and one large extracellular domain (ECD). In response to extracellular acidification, the TMD-ECD rearranges to allow the opening of the channel pore. Several splice variants of PAC have been identified, but whether they affect the gating or the pharmacology of the channel is poorly defined. Existing synthetic PAC modulators suffer from limited selectivity, low affinity, and/or poor pharmacokinetic profiles. Additionally, PAC regulation by physiological factors is poorly understood; the specific gating changes in response to different pHe were only recently identified (Sci Adv. 2022;8(5)). The importance of other physiological factors, for example phosphorylation and modulation by common channel regulators such as the signalling lipid phosphatidyl inositol diphosphate (PIP2) and diacylglycerol (DAG), are largely unexplored. Our preliminary computational (molecular docking) and mutagenesis experiments show that the channel’s proton binding site may constitute a site of action for existing therapeutic drugs which may form the basis for the design of novel, potent small molecule modulators of PAC function.
The overall aim of this DPhil project is to advance our understanding of how the PAC channel is modulated pharmacologically and by endogenous biological factors such as PIP2 and DAG and to elucidate the potential for targeting PAC in pathological states associated with altered pHe. Emphasis will be given to the role of PAC in contractile pericytes and the possible involvement in ischaemia-induced capillary constriction. The project will foster our understanding of how vascular tone is modulated by maladaptive acidosis, possibly revealing a new therapeutic target for disturbances of acid-base balance.
The project closely embraces the MRC priority area of ‘molecular and cellular medicine’. The project offers the student an exciting and cross-disciplinary training in cutting-edge approaches in a world-class academic and industrial environment. The varied skill sets and professional experiences the student will acquire will place the student in the perfect position to move forwards into the next stages of their career.
Apply using course: DPhil in Pharmacology
