My research focus is to understand the mechanisms which elicit and maintain hormone-induced Ca2+ oscillations in the liver. Hepatocytes display stimulus-strength regulated Ca2+ oscillations and waves when challenged with hormones, such as vasopressin and glucagon, which couple to PLC-linked GPCRs. My research utilizes single cell imaging techniques and photorelease of caged IP3 to dissect the mechanisms regulating oscillations. I have demonstrated multiple proteins involved in the Ca2+ signalling pathway are regulated by PKC which provides both positive and negative feedback mechanisms to shape Ca2+ responses.
More recently my research has focused on Ca2+ dysfunction and the role this plays in the pathogenesis of disease states such as alcoholic and non-alcoholic fatty liver disease. Many primary functions of the liver are regulated by signaling mechanisms that manifest as cytosolic Ca2+ ([Ca2+]c) oscillations, including glucose metabolism, mitochondrial physiology and gene expression. I have shown, chronic alcohol consumption sensitizes hepatocytes to PLC-linked hormones, potentiating Ca2+ signals and increasing cellular oxidative stress. My current research aims to delineate the effects of high fat diet on hormone-dependent calcium signaling in hepatocytes, in particular how these contribute to the dysregulation glucose homeostasis and the role this plays in the development of hepatic insulin resistance and diabetes.
PhD, 2007, University of Leicester Bsc, 2000, University of West England
Bartlett PJ, Cloete I, Syned J and Thomas AP. IP3-Dependent Ca2+ oscillations
switch into a dual oscillator mechanism in the presence of PLC-linked hormones. (2020)
Bartlett PJ, Antony AN, Agarwal A, Hilly M, Prince VL, Combettes L, Hoek JB and
Gaspers LD. Chronic alcohol feeding potentiates hormone-induced calcium signaling in
hepatocytes. (2017) Journal of Physiology, 5;595(10):3143-3164.
Garcia CR, Alves E, Pereira PH, Bartlett PJ, Thomas AP, Mikoshiba K, Plattner H,
Sibley LD. InsP3 Signaling in Apicomplexan Parasites. (2017) Current Topical Medicinal
Bartlett PJ, Metzger W, Gaspers L.D, Thomas A.P. Differential regulation of
multiple steps in inositol 1,4,5- trisphosphate signaling by protein kinase C shapes
hormone-stimulated Ca2+ oscillations. (2015) J. Biol. Chem. 290(30):18519-18533.
Gaspers LD, Bartlett PJ*, Politi A, Burnett P, Metzger W, Johnston J, Joseph SK,
Hofer T, Thomas AP. (2014) Hormone-induced calcium oscillations depend on cross-coupling
with inositol 1,4,5-trisphosphate oscillations. Cell Reports 20;9(4):1209-1218 * co first
Bartlett, PJ, Gaspers, LD, Pierobon, N and Thomas AP. Calcium-dependent regulation
of glucose homeostasis in the liver. (2014) Cell Calcium, 55, 306-316.
Bartlett PJ, Garcia CR, Thomas AP. Single Cell Calcium Imaging in Malaria.
(2014). Methods in Malaria Research 6th Edition. Edited by Kirsten Moll, Inger
Hedvig Perlmann,Artur Scherf and Mats Wahlgren. Publisher: Malaria Reference and Reagent
Resource Center, Manassas
Huang G, Bartlett PJ, Thomas AP, Moreno SN, Docampo R. Acidocalcisomes of
Trypanosoma brucei have an inositol 1,4,5-trisphosphate receptor that is required for
growth and infectivity. (2013) Proc. Natl. Acad. Sci. 110, 1887-1892.
Alves E. Bartlett PJ, Garcia CR, Thomas AP. Melatonin and IP3-induced Ca2+ release
from intracellular stores in the malaria parasite Plasmodium falciparum within infected
red blood cells. (2011) J. Biol. Chem. 286, 5905-5912.
Bartlett PJ, Young KW, Nahorski SR and Challiss RA. Single cell analysis and
temporal profiling of agonist-mediated inositol 1,4,5-trisphosphate, Ca2+,
and protein kinase C signaling using fluorescent biosensors. (2005) J. Biol. Chem.
Areas Of Interest
My research interrogates the mechanisms which elicit and maintain hormone-induced Ca2+ oscillations in primary hepatocytes. In liver hepatocytes hormonal regulation of Ca2+ signalling underlies many of the primary functions of the organ including glucose metabolism, mitochondrial physiology and gene expression. Hormones which couple to phospholipase C, Gq-linked GPCRs, hydrolysis the membrane phosphoinositide lipid PIP2 to generate IP3 and DAG, which in turn regulate cell function via Ca2+ release and PKC activation. Hepatocytes display stimulus-strength regulated Ca2+ oscillations and waves importantly the pattern of intracellular Ca2+ fluctuations encodes complex spatial and temporal information to regulate cell function. We utilize single cell digital fluorescent imaging techniques combined with biochemical techniques to dissect the mechanisms which generate, maintain and regulate Ca2+ oscillations. These studies address the ongoing debate, whether Ca2+ oscillations arise due to Ca2+ feedback on the IP3 receptor or as a consequence of fluctuations in IP3, hence phospholipase C activity. Our studies have provided compelling evidence that Ca2+ oscillations in hepatocytes depend on IP3 fluctuations arising from positive Ca2+ feedback on PLC.
Ca2+ dysregulation has been implicated in the pathology of many diseases due to alterations in gene expression, increases in reactive oxygen species and cellular stress and induction of pro-apoptotic signalling. Thus, beyond the study of the basic mechanisms driving Ca2+ oscillations, my research also focuses on Ca2+ signalling dysfunction and the role this plays in the pathogenesis of disease states such as alcoholic and non-alcoholic fatty liver disease. We have shown, chronic alcohol consumption sensitizes hepatocytes to PLC-linked hormones, potentiating Ca2+ signals and increasing cellular oxidative stress. My current research I aim to delineate the effects of high fat diet on hormone-dependent Ca2+ signaling in particular how these contribute to the dysregulation glucose homeostasis and the role this plays in the development of hepatic insulin resistance and diabetes.
I also leverage my understanding of mammalian GPCR-dependent signaling to interrogate the role of GPCR pathways in the malaria parasite. We have shown malaria parasites entrain their red blood cell life cycle phase by responding to the host hormone melatonin. This research has challenged the dogma that malaria parasites do not possess intracellular Ca2+ release channels by demonstrating melatonin evokes intracellular Ca2+ responses in malaria and generates inositol phospholipids. Moreover, IP3 uncaging elicits a calcium response in malaria. I have also evidenced caged IP3 dependent Ca2+ release in Toxoplasma gondii and Trypanosoma brucei (two other human pathogens) indicating a canonical IP3-dependent signalling pathway is conserved in protist parasites. We are currently characterising this pathway with a view to identifying novel drug targets for malaria treatment