Phosphodiesterase 1 signalsomes: the utility of peptide disruptors for pulmonary arterial hypertension

The ubiquitously expressed second messenger, cyclic AMP (cAMP), plays a key role in controlling cellular responses that regulate a wide number of physiological processes throughout the body. Compartmentalization of cAMP is key in the spatio-temporal control of cAMP dynamics that determines its function in cells. Phosphodiesterases (PDEs), which hydrolyse cAMP, underpin compartmentalization of the second messenger by forming specific protein complexes (signalsomes) that restrict cAMP within subcellular compartments. Such protein complexes also include membrane-bound proteins (G protein-coupled receptors), scaffolding proteins (A kinase anchoring proteins) and downstream mediators (protein kinase A) of cAMP. Identification of PDE signalsomes has uncovered PDE-specific protein complexes, many of which are implicated in heart failure, cancer and cognitive decline. Mapping of PDE-protein interfaces and the rational design of novel peptide disrupters has uncovered the role of such complexes in cell function. Cell permeable peptide disrupters, which have higher target specificity to traditional small molecules, represent an exciting area of drug discovery.

We have shown a specific PDE family member, PDE1C, plays a pivotal role in shaping cAMP gradients in pulmonary artery smooth muscle cells (PASMCs) and its increased expression and activity accounts for lower cAMP and increased PASMC proliferation in pulmonary arterial hypertension (PAH, Murray et al., 2007). More recently we find PDE1C limits the efficacy of prostacyclin analogues, which are currently clinically approved for PAH, by interacting with the prostacyclin (IP) receptor and enhancing its degradation. Using a variety of molecular and biochemical approaches together with 'peptide chip' technology (Professor Baillie, Blair et al., 2019), this project aims to define the interacting proteins, subcellular localisation and function of this exciting newly discovered PDE1C/IP signalsome. Furthermore, we will develop novel peptide disruptors, including cell permeable cyclic peptides (Dr Houssen, Idress et al., 2020) using synthetic biology and chemistry, to elucidate the functional significance of the PDE1C/IP complex in PASMC and its role in PAH. This PhD project brings together areas of expertise in pulmonary physiology, pharmacology, biochemistry, synthetic biology and chemistry from the University of Aberdeen and University of Glasgow, which will offer an optimal training environment and provide the student with a set of highly desirable skills. It is expected that completion of the aims will advance our understanding of the cellular function of PDE1 signalsomes and uncover novel peptide therapeutics for diseases.