My laboratory is particularly interested in posttranscriptional and posttranslational mechanisms of ion channel regulation and their role in the dynamic control of cellular excitability and systems level function in health and disease.
How we think, eat, breathe and move is ultimately controlled by changes in the electrical activity of cells in our body.
My lab is particularly interested in how potassium ion channels that control cell excitability, are regulated by both post-transcriptional and post-translational mechanisms and importantly how dysregulation may lead to disease.
We take an Integrative Physiology approach examining from the level of single ion channel proteins to whole body function.
Work is currently focused in two main areas:
Dysregulation of calcium-activated (BK) potassium channels may lead to major human disorders such as obesity, diabetes and high blood pressure. Understanding how these channels are regulated by both environmental (e.g. diet, stress, drugs) as well as genetic (e.g gene mutations) factors is thus crucial to understanding both the causes of such diseases and allow us to define new therapeutic strategies to treat them.
Addressing these issues also underpins one of the major challenges in post-genomic biology: understanding how we generate physiological diversity from a limited genome.
My laboratory focuses on the role of the major post-transcriptional ( e.g. alternative pre mRNA splicing) and post-translational (e.g. phosphorylation, S-acylation (palmitoylation)) drivers for generating proteomic diversity, in controlling BK channel properties and physiology.
We are trying to understand how interaction between these processes and the physiological consequence of changes in these pathways controls defined physiological systems.
In particular, recent work has focussed on S-acylation (palmitoylation), a reversible post-translational lipid modification, that controls the trafficking of BK channels to the cell surface as well as their activity and regulation by phosphorylation-dependent signalling pathways.
Funded by the Wellcome Trust and British Heart Foundation, we take a multidisciplinary approach to understand how S-acylation controls channel properties and physiology from analysis of single ion channel signalling complexes to analysis of channel function at the systems level using conditional knockout strategies.
Our ability to respond and cope with stress is ultimately controlled by the activity of celsl within the neuroendocrine stress axis: the hypothalamic-pituitary-adrenal (HPA) axis.
A bit of stress is good for us but prolonged or excessive stress can lead to major cardiovascular, metabolic and affective disorders. The stress axis is controlled by both a 24hr (circadian) and an ~ hourly (ultradian) rhythm and disruption of the rhythmical release of stress hormones is associated with disease.
In a Medical Research Council- funded programme we are trying to understand the role of the excitable corticotroph cells in the pituitary in the control of the ultradian rhythm and gain better insights into how we may more effectively treat stress-related disorders.
Illison J, Tian L, McClafferty H, Werno M, Chamberlain LH, Leiss V, Sassmann A, Offermanns S, Ruth P, Shipston MJ, Lukowski R. (2016) Obesogenic and Diabetogenic Effects of High-Calorie Nutrition Require Adipocyte BK Channels. Diabetes. 65(12):3621-3635. (E-pub)
Duncan PJ, Tabak J, Ruth P, Bertram R, Shipston MJ (2016) Glucocorticoids inhibit CRH/AVP-evoked bursting activity of male murine anterior pituitary corticotrophs. Endocrinology. 157(8):3108-21
Duncan PJ, Sengül S, Tabak J, Ruth P, Bertram R, Shipston MJ. (2015) Large conductance Ca 2+ -activated K+(BK) channels promote secretagogue-induced transition from spiking to bursting in murine anterior pituitary corticotrophs. J Physiol. 593:1197-1211
Chamberlain LH & Shipston MJ (2015) The physiology of protein S-acylation. Physiological Reviews 95:341-376
Howie J, Reilly L, Fraser NJ, Vlachaki Walker JM, Wypijewski KJ, Ashford ML, Calaghan SC, McClafferty H, Tian L, Shipston MJ, Boguslavskyi A, Shattock MJ, Fuller W. (2014) Substrate recognition by the cell surface palmitoyl transferase DHHC5. Proc Natl Acad Sci U S A. 111:17534-9
Shipston MJ. (2014) Ion channel regulation by protein S-acylation. J Gen Physiol. 143(6):659-78
Chen L, Bi D, Tian L, McClafferty H, Steeb F, Ruth P, Knaus HG, Shipston MJ. (2013) Palmitoylation of the β4-subunit regulates surface expression of large conductance calcium-activated potassium channel splice variants J Biol Chem 288:13136-13144
Zhou X, Wulfsen I, Korth M, McClafferty H, Lukowski R, Shipston MJ, Ruth P, Dobrev D, Wieland T. (2012) Palmitoylation and Membrane Association of STREX Controls BK Channel Regulation by Protein Kinase C. J Biol Chem 287:32161-32171
Tian, L., H. McClafferty, H.-G. Knaus, P. Ruth and M.J. Shipston. (2012). Distinct Acyl Protein Transferases and Thioesterases Control Surface Expression of Calcium-activated Potassium Channels. J Biol Chem 287(18): 14718-14725.
Liang Z, Chen L, McClafferty H, Lukowski R, Macgregor D, King JT, Rizzi S, Sausbier M, McCobb DP, Knaus HG, Ruth P, Shipston MJ (2011) Control of the hypothalmo-pituitary-adrenal axis activity by the intermediate conductance calcium-activated potassium channel, SK4. J Physiol. 589:5965-86
Jeffries, O., Geiger, N., Rowe, I.C.M., Tian, L., McClafferty, H., Chen, L., Bi, D., Knaus, H.G., Ruth, P., & Shipston, M.J. (2010) Palmitoylation of the S0-S1 linker regulates cell surface expression of voltage- and calcium- activated potassium channels. J Biol Chem 285:33307-33314
Chen, L., Jeffries, O., Rowe, I.C.M., Liang, Z., Knaus, H-G., Ruth, P & Shipston M.J. (2010) Membrane trafficking of large conductance calcium-activated potassium channels is regulated by alternative splicing of a transplantable, acidic trafficking motif in the RCK1-RCK2 linker. J Biol Chem 285:23265-23275.
Tian, L., McClafferty, H., Jeffries, O & Shipston M.J. (2010) Multiple palmitoyltransferases are required for palmitoylation-dependent regulation of large conductance calcium- and voltage- activated potassium channels. J Biol Chem 285: 23954-23962.
Tian, l., Jeffries, O.J., McClafferty, H., Molyvdas, A., Rowe, I.C.M. Saleem, F., Chen L., Greaves, J., Chamberlain, L.H., Knaus, H.G., Ruth P., & Shipston, M.J. (2008) Palmitoylation gates phosphorylation-dependent regulation of BK potassium channels. Proc. Natl. Acad. Sci. USA 105:21006-21011.
McCartney C.E., McClafferty H., Huibant J-M., Rowan E.G., Shipston M.J. & Rowe I.C.M. (2005). A cysteine rich motif confers hypoxia sensitivity to mammalian BK channel ?-subunits. Proc. Natl. Acad. Sci. U.S.A. 102:17870-17876
Tian L., Coghill L. S., McClafferty H., MacDonald S. H-F., Antoni F. A., Ruth P., Knaus H-G. & Shipston M. J. (2004) Distinct stoichiometry of BKCa channel tetramer phosphorylation specifies channel activation and inhibition by cAMP-dependent protein kinase. Proc. Natl. Acad. Sci. U.S.A. 101:11897-11902
Sausbier, M., Hu, H., Arntz, C., Feil, S., Kamm, S., Adelsberger, H., Sausbier, U., Sailer, C. A., Feil, R., Hofmann, F., Korth M., Shipston M .J., Knaus H-G., Wolfer D. P., Pedroarena C. M., Storm J. F. & Ruth P.(2004) Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proc. Natl. Acad. Sci. U.S.A.101:9474-9478
Duncan, R.R., Grieves, J., Wiegand, U.K., Matskevich, I., Bodammer, G., Apps, D.K., Shipston, M.J. and Chow, R.H. (2003) Functional and spatial segregation of secretory vesicle pools according to vesicle age. Nature 422:176-180 [Front cover]