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CDB Seminars
All welcome

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All Seminars are held in the Gavin De Beer Lecture Theatre, Anatomy Building, Thursday 1-2pm

5 March: András Szabó (Mayor lab) / Pedro Pereira (Henriques’ lab)

12 March: Jose Gomez (Jessen lab)/Sara Maffioletti (Tedesco lab)

26 March: Lizzie Yates (Patel lab) / Melissa Barber (Parnavelas lab)

9 April: Zeki lab –TBC/ Francis Carpenter (Caswell Barry lab)

23 April: Florent Peglion (Nate Guring lab)/Michele Sammut (Barrios lab, now in Poole lab) 

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Prof Sandip Patel

Prof Sandip Patel

Professor of Cell Signalling

patel.s@ucl.ac.uk

Telephone:
Office: 020 7679 4437
(Int: 34437)

The Patel lab: Ca2+ signalling through acidic organelles

Our lab focuses on the role of acidic organelles, such as lysosomes, in Ca2+ signalling in both health and disease. See the outreach section for a plain English summary.


Patel Figure 1


Background

Changes in cytosolic Ca2+ form the basis of a ubiquitous, evolutionary conserved signalling pathway. These Ca2+ signals drive many, if not all cellular processes from the very start of life (fertilisation), during vital processes such as neurotransmission, through to death (apoptosis). It is now clear that so-called “acidic Ca2+ stores” dynamically regulate cytosolic Ca2+ levels, both in isolation and in conjunction with the better-characterised Ca2+ stores of the endoplasmic reticulum. Acidic Ca2+ stores is an umbrella term that describes a cross-kingdom collection of morphologically distinct-yet-functionally related organelles united by their acid and Ca2+-rich interior. Lysosomes and lysosome-related organelles are key acidic Ca2+ stores that are considered functionally related to acidocalcisomes, vacuoles, endosomes, secretory granules and the Golgi complex. The Ca2+ mobilising messenger NAADP plays a critical role in controlling acidic Ca2+ store signalling.

Vision

We are i) defining the Ca2+ signalling “toolkit” (channels, transporters) of acidic Ca2+ stores at the molecular level and their evolutionary origins (form), ii) probing their physiological roles in processes such as membrane trafficking and cell migration (function) and iii) investigating how deviant signalling through these organelles can precipitate disorders such as Parkinson disease (failure).

Approach

Our work is interdisciplinary, encompassing both “wet” (molecular, cell and structural biology) and “dry” (bioinformatics, phylogenetics and computational modelling) approaches in a highly collaborative and international context.

NAADP: An unusual Ca2+ mobilizing messenger

NAADP is a potent Ca2+ mobilising messenger, discovered in the 1990s by Hon Cheung Lee and colleagues. Over the last 15 years or so, we have played a central role in defining its mechanism of action using many model systems spanning from sea urchin eggs to primary human fibroblasts. In early work, we: i) identified and characterised the binding properties of NAADP receptors; ii) showed that NAADP is highly unusual in activating Ca2+-permeable channels located on non-canonical, acidic Ca2+ stores such as lysosomes and lysosome-like organelles; iii) quantified cellular NAADP levels and identified NAADP generating signals, such as the hormones and neurotransmitters; iv) identified and characterised NAADP synthesizing enzymes – the ADP-ribosyl cyclases - from both invertebrate and vertebrate systems and v) extended the actions of NAADP to the nervous system. iia


Patel, S., G.C.Churchill, T.Sharp, and A.Galione. 2000. Widespread distribution of binding sites for the novel Ca2+-mobilizing messenger, nicotinic acid adenine dinucleotide phosphate, in the brain. J. Biol. Chem. 275:36495-36497.

Berridge, G., G.Dickinson, J.Parrington, A.Galione, and S.Patel. 2002. Solubilization of receptors for the novel Ca2+-mobilizing messenger, nicotinic acid adenine dinucleotide phosphate. J. Biol. Chem. 277:43717-43723.

Churchill, G.C., Y.Okada, J.M.Thomas, A.A.Genazzani, S.Patel, and A.Galione. 2002. NAADP mobilizes Ca2+ from reserve granules, lysosome-related organelles, in sea urchin eggs. Cell 111:703-708.

Churamani, D., E.A.Carrey, G.D.Dickinson, and S.Patel. 2004. Determination of cellular nicotinic acid-adenine dinucleotide phosphate (NAADP) levels. Biochem. J. 380:449-454.

Yamasaki, M., J.T.Thomas, G.C.Churchill, C.Garnham, A.L.Lewis, J.M.Cancela, S.Patel, and A.Galione. 2005. Role of NAADP and cADPR in the induction and maintenance of agonist-evoked Ca2+ Spiking in mouse pancreatic acinar cells. Curr. Biol. 15:874-878.

Brailoiu, E., J.L.Hoard, C.M.Filipeanu, G.C.Brailoiu, S.L.Dun, S.Patel, and N.J.Dun. 2005. Nicotinic acid adenine dinucleotide phosphate potentiates neurite outgrowth. J. Biol. Chem. 280:5646-5650.

Churamani, D., M.J.Boulware, T.J.Geach, A.C.Martin, G.W.Moy, Y.H.Su, V.D.Vacquier, J.S.Marchant, L.Dale, and S.Patel. 2007. Molecular characterization of a novel intracellular ADP-ribosyl cyclase. PLoS. ONE. 2:e797.

Pandey, V., C.C.Chuang, A.M.Lewis, P.Aley, E.Brailoiu, N.Dun, G.C.Churchill, and S.Patel. 2009. Recruitment of NAADP-sensitive acidic Ca2+ stores by glutamate. Biochem. J. 422:503-512.

The two-pore channels (TPCs)

In 2009, we were one of three groups that converged on the TPCs as the long-sought-after target channels for NAADP. TPCs have a duplicated domain architecture comprising two concatenated voltage-gated ion channel-like repeats, each containing 6 transmembrane regions and a re-entrant pore loop. They likely dimerise to form the characteristic pseudotetrameric arrangement typical of the voltage-gated ion channel superfamily to which TPCs belong. We showed that TPCs localise to the endolysosomal system and applied loss- and gain-of function approaches, together with Ca2+ imaging and electrophysiology (with Rahman and Muallem), to show that TPCs are likely the pore-forming subunit of NAADP-gated, Ca2+-permeable channels. Our work with Marchant suggests that NAADP does not bind directly to TPCs, but instead to closely associated NAADP-binding protein(s). Modifiers of voltage-gated Ca2+ and Na+ channels also block TPCs, possibly though a common binding site. We are currently performing structure-function analyses of TPCs.

Researchfig2

Brailoiu, E., D.Churamani, X.Cai, M.G.Schrlau, G.C.Brailoiu, X.Gao, R.Hooper, M.J.Boulware, N.J.Dun, J.S.Marchant, and S.Patel. 2009. Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling. J. Cell Biol. 186:201-209.

Brailoiu, E., T.Rahman, D.Churamani, D.L.Prole, G.C.Brailoiu, R.Hooper, C.W.Taylor, and S.Patel. 2010b. An NAADP-gated two-pore channel targeted to the plasma membrane uncouples triggering from amplifying Ca2+ signals. J. Biol. Chem. 285:38511-38516.

Hooper, R., D.Churamani, E.Brailoiu, C.W.Taylor, and S.Patel. 2011. Membrane topology of NAADP-sensitive two-pore channels and their regulation by N-linked glycosylation. J. Biol. Chem. 286:9141-9149.

Churamani, D., R.Hooper, E.Brailoiu, and S.Patel. 2012. Domain assembly of NAADP-gated two-pore channels. Biochem. J. 441:317-323.

Lin-Moshier, Y., T.F.Walseth, D.Churamani, S.M.Davidson, J.T.Slama, R.Hooper, E.Brailoiu, S.Patel, and J.S.Marchant. 2012. Photoaffinity labeling of nicotinic acid adenine dinucleotide phosphate (NAADP) targets in mammalian cells. J. Biol. Chem. 287:2296-2307.

Jha, A., M.Ahuja, S.Patel, E.Brailoiu, and S.Muallem. 2014. Convergent Regulation of the Lysosomal Two-Pore Channel-2 by Mg2+, NAADP, PI(3,5)P2 and Multiple Protein Kinases. EMBO J. 33:501-511

Rahman, T., X.Cai, G.C.Brailoiu, M.E.Abood, E.Brailoiu, and S.Patel. 2014. Two-pore channels provide insight into the evolution of voltage-gated Ca2+ and Na+ channels. Sci. Signal. 7:ra109.

Inter-organellar crosstalk

NAADP is often described as “trigger” for Ca2+ signalling. This is because the Ca2+ signals it evokes from acidic organelles can be amplified by neighbouring channels on the ER, likely through the process of Ca2+-induced Ca2+-release. We have proposed that such “chatter” might occur at membrane contact sites between the ER and the endolysosomal system. Membrane contact sites are regions of close apposition where different membranes come in close contact (<30 nm) but do not fuse. With Futter we have identified membrane contact sites between the lysosomes and ER. Computational modelling with Sneyd has provided insight into Ca2+ signalling at these junctions. We are currently investigating the properties of these junctions.

Research3a


Patel, S., and E.Brailoiu. 2012. Triggering of Ca2+ signals by NAADP-gated two-pore channels. A role for membrane contact sites? Biochem. Soc. Trans. 40:153-157.

Kilpatrick, B.S., E.R.Eden, A.H.Schapira, C.E.Futter, and S.Patel. 2013. Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals. J. Cell Sci. 126:60-66.

Penny, C.J., B.S.Kilpatrick, J.M.Han, J.Sneyd, and S.Patel. 2014. A computational model of lysosome-ER Ca2+ microdomains. J. Cell Sci. 127:2934-2943.

Membrane trafficking

It is likely that the local Ca2+ signals derived from acidic organelles might act in their own right to drive physiological processes. Indeed, it has been known for some time that local Ca2+ signals regulate various trafficking events within the endolysosomal system. With Marchant, we have shown that TPCs associate with a variety of proteins involved in membrane trafficking (such as Rab GTPases) to regulate endolysosomal morphology. We are currently defining the mechanisms by which TPCs regulate membrane traffic. membrane trafficking


Lin-Moshier, Y., M.V.Keebler, R.Hooper, M.J.Boulware, X.Liu, D.Churamani, M.E.Abood, T.F.Walseth, E.Brailoiu, S.Patel, and J.S.Marchant. 2014. The two-pore channel (TPC) interactome unmasks isoform-specific roles for TPCs in endolysosomal morphology and cell pigmentation. Proc. Natl. Acad. Sci. 111:13087-13092.

Parkinson disease

There is an increasing appreciation of the role of lysosomal dysfunction in neurodegenerative disorders such as Alzheimer’s and Parkinson disease. With Schapira, we have recently identified Ca2+-dependent lysosomal trafficking defects in fibroblasts from Parkinson disease patients. We showed that chemical or molecular inhibition of the NAADP pathway restores endocytic “well-being”. We are currently exploring whether the NAADP-signalling pathway might therefore represent a novel therapeutic target in Parkinson disease. Researchfig5

Hockey, L. N., Kilpatrick, B. S., Eden, E. R., Lin-Moshier, Y., Brailoiu, G. C., Brailoiu, E., Futter, C., Schapira, A. H., Marchant, J. S. and Patel, S. (2015) Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by two-pore channel 2 inhibition. J.Cell Sci. 128, 232-238

Evolution

Despite their diversity, acidic Ca2+ stores may function similarly across the natural world in processes such as signalling, membrane traffic and secretion. TPCs are particularly interesting in an evolutionary context in terms of their phylogenomic profile (i.e. the presence of their genes in specific organisms) and their putative structure. Most deuterostome animals possess three TPC isoforms but there is highly unusual, lineage-specific loss of TPC3 in certain primates (including humans) and rodents. Their duplicated domain organisation indicates that they may be descendants of the key evolutionary intermediate between one- and four-domain members of the voltage-gated ion channel superfamily. With Cai, we have established the phylogenetic relationship between multi-domain voltage-gated ion channels, and recently identified a novel clade of TPCs in unicellular organisms with predicted properties similar to voltage-gated Ca2+ channels. We are exploring the evolutionary trajectory for TPCs and their related channels.

Evolution


Patel, S., and R.Docampo. 2010. Acidic calcium stores open for business: expanding the potential for intracellular Ca2+ signaling. Trends Cell Biol. 20:277-286.

Brailoiu, E., R.Hooper, X.Cai, G.C.Brailoiu, M.V.Keebler, N.J.Dun, J.S.Marchant, and S.Patel. 2010. An ancestral deuterostome family of two-pore channels mediate nicotinic acid adenine dinucleotide phosphate-dependent calcium release from acidic organelles. J. Biol. Chem. 285:2897-2901.

Cai, X., and S.Patel. 2010. Degeneration of an intracellular ion channel in the primate lineage by relaxation of selective constraints. Mol. Biol. Evol. 27:2352-2359.

Patel, S., and S.Muallem. 2011. Acidic Ca2+ stores come to the fore. Cell Calcium 50:109-112.

Rahman, T., X.Cai, G.C.Brailoiu, M.E.Abood, E.Brailoiu, and S.Patel. 2014. Two-pore channels provide insight into the evolution of voltage-gated Ca2+ and Na+ channels. Sci. Signal. 7:ra109.

Patel, S., and X.Cai. 2015. Evolution of acid Ca2+ stores and their resident Ca2+-permeable channels. Cell Calcium.

Sandip Patel

patel


Principal investigator

Bethan S. Kilpatrick

Bethan Kilpatrick


Post doc

Manuela Melchionda

Melchionda


Post doc

Stephen Mullin

Stephen Mullin


PhD student (Primary supervisor: Anthony. H. Schapira)

Christopher J. Penny

Christopher Penny


PhD student

Elizabeth Yates

Elizabeth Yates


PhD student

Alumini

Leanne Hockey (MSc student, 2011 – 2012)

Dev Churamani, (PhD student, 2002 – 2005; Post doc, 2006 – 2012)

Suchita Deo (MSc student, 2010 – 2011)

Robert Hooper (PhD student; 2008 – 2011)

Latha Ramakrishnan (PhD student; 2007 – 2010)

George Dickinson (Post doc, 2002 - 2004; Post doc 2008 – 2010)

Vinita Pandey (Post doc, 2004 – 2006)

Dayle Hogg (Post doc, 2000 – 2001)

Georgina Berridge (Research assistant; 2000 – 2001)

Sandip Patel obtained a BSc in Medical Biochemistry from the University of Birmingham in 1992, and a PhD in Pharmacology from Cambridge University in 1995 under the supervision of Prof. Colin W. Taylor.

He was awarded a Wellcome Trust “Prize” International Travel Fellowship in 1996. This allowed him to do post-doctoral work with Prof. Andrew P. Thomas, initially at Thomas Jefferson University and then at the University of Medicine and Dentistry of New Jersey (now Rutgers University) in the USA (1996-1998). He spent the last year of his fellowship (1999-2000) with Prof Antony Galione at Oxford University where Sandip developed his interests in NAADP.

Sandip was awarded a Wellcome Trust Career Development Fellowship in 2000 which allowed him to set up his own lab at Oxford. He also held the Hayward Junior Research Fellowship at Oriel College at this time. In 2001, he re-located the lab to University College London and was awarded a lectureship. Sandip was promoted to Reader in 2007 and Professor in 2011.

Sandip was Vice-chair of the Signalling Panel of Biochemical Society (2009-2012) and a member of the Editorial boards of Biology of the Cell (2003-2006), the Biochemical Journal (2004-2011), Cell Calcium (2007- ) and Messenger (2012-).

He was elected a Fellow of the Society of Biology (FSB) in 2013.

Our lab collaborates extensively at the local, national and international level.

Collaborators World Map
University College London  
Leslie Dale  
Michael R. Duchen  
Sean M. Davidson  
Clare E. Futter  
Roberto Mayor  
Anthony H. Schapira  
Bonnie A. Wallace  
   
UK
 
Grant C. Churchill Oxford University
Jon Pittman Manchester University
Taufiq Rahman Cambridge University
   
International  
Eugen Brailoiu Temple University, USA
Xinjiang Cai Rutgers University, USA
Jonathan Marchant University of Minnesota, USA
Shmuel Muallem NIH, USA
Israel Sekler
Ben-Gurion University of the Negev, Israel
Soraya Smaili Federal University of São Paulo, Brazil
James Sneyd University of Auckland, New Zealand
Mathias Ziegler University of Bergen, Norway


Cell Calcium cvr Science Signalling

Research Publications


Retrieving data...

Our published work is regularly highlighted or attracts commentaries by our peers.

Hockey, L. N., Kilpatrick, B. S., Eden, E. R., Lin-Moshier, Y., Brailoiu, G. C., Brailoiu, E., Futter, C., Schapira, A. H., Marchant, J. S. and Patel, S. (2015) Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by two-pore channel 2 inhibition. J.Cell Sci. 128, 232-238

Highlighted as an “In This Issue” article. “Two-pore channels in Parkinson disease” http://jcs.biologists.org/content/128/2/e0204.full

Rahman, T., Cai, X., Brailoiu, G. C., Abood, M. E., Brailoiu, E. and Patel, S. (2014) Two-pore channels provide insight into the evolution of voltage-gated Ca2+ and Na+ channels. Sci.Signal. 7, ra109

Features on front cover.
Commentary: Adler, E. M. (2015) Of ELIC and evolution J.Gen.Physiol 145, 1-2

Penny, C. J., Kilpatrick, B. S., Han, J. M., Sneyd, J. and Patel, S. (2014) A computational model of lysosome-ER Ca2+ microdomains. J.Cell Sci. 127, 2934-2943

Commentary: Dupont G: F1000Prime Recommendation of [Penny CJ et al., J Cell Sci 2014]. In F1000Prime, 23 Jun 2014; DOI: 10.3410/f.718339757.793496449. F1000Prime.com/718339757#eval793496449

Jha, A., Ahuja, M., Patel, S., Brailoiu, E. and Muallem, S. (2014) Convergent Regulation of the Lysosomal Two-Pore Channel-2 by Mg2+, NAADP, PI(3,5)P2 and Multiple Protein Kinases. EMBO J. 33, 501-511

Commentary: Tepikin A: F1000Prime Recommendation of [Jha A et al., EMBO J 2014, 33(5):501-11]. In F1000Prime, 07 May 2014; DOI: 10.3410/f.718269090.793494576. F1000Prime.com/718269090#eval793494576

Churamani, D., Hooper, R., Rahman, T., Brailoiu, E. and Patel, S. (2013) The N-terminal region of two-pore channel 1 regulates trafficking and activation by NAADP. Biochem.J. 453, 147-151

Commentary: Tepikin A: F1000Prime Recommendation of [Churamani D et al., Biochem J 2013, 453(1):147-51]. In F1000Prime, 30 May 2013; DOI: 10.3410/f.718012458.793477168. F1000Prime.com/718012458#eval793477168
Commentary: Docampo R: F1000Prime Recommendation of [Churamani D et al., Biochem J 2013, 453(1):147-51]. In F1000Prime, 20 Jun 2013; DOI: 10.3410/f.718012458.793478401. F1000Prime.com/718012458#eval793478401
Commentary: Guse, A. H. (2013) N-terminal tagging of two-pore channels interferes with NAADP action Biochem.J. 453, e1-e2

Kilpatrick, B. S., Eden, E. R., Schapira, A. H., Futter, C. E. and Patel, S. (2013) Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals. J.Cell Sci. 126, 60-66

Commentary: Petersen O: F1000Prime Recommendation of [Kilpatrick BS et al., J Cell Sci 2013, 126(Pt 1):60-6]. In F1000Prime, 05 Nov 2013; DOI: 10.3410/f.718157884.793486093. F1000Prime.com/718157884#eval793486093

Lin-Moshier, Y., Walseth, T. F., Churamani, D., Davidson, S. M., Slama, J. T., Hooper, R., Brailoiu, E., Patel, S. and Marchant, J. S. (2012) Photoaffinity labeling of nicotinic acid adenine dinucleotide phosphate (NAADP) targets in mammalian cells. J.Biol.Chem. 287, 2296-2307

Paper of the week.
Commentary: Guse, A. H. (2012) Linking NAADP to Ion Channel Activity: A Unifying Hypothesis Sci.Signal. 5, e18

Brailoiu, E., Churamani, D., Cai, X., Schrlau, M. G., Brailoiu, G. C., Gao, X., Hooper, R., Boulware, M. J., Dun, N. J., Marchant, J. S. and Patel, S. (2009) Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling. J.Cell Biol. 186, 201-209

Highlighted as an “In This Issue” article. “Calcium’s route to freedom” http://jcb.rupress.org/content/186/2/164.2.full.pdf+html

Brailoiu, E., Churamani, D., Pandey, V., Brailoiu, G. C., Tuluc, F., Patel, S. and Dun, N. J. (2006) Messenger-specific role for NAADP in neuronal differentiation. J.Biol.Chem. 281, 15923-15928

Commentary: Galione A: F1000Prime Recommendation of [Brailoiu E et al., J Biol Chem 2006, 281(23):15923-8]. In F1000Prime, 21 Apr 2006; DOI: 10.3410/f.1014311.371942. F1000Prime.com/1014311#eval371942

Brailoiu, E., Hoard, J. L., Filipeanu, C. M., Brailoiu, G. C., Dun, S. L., Patel, S. and Dun, N. J. (2005) NAADP potentiates neurite outgrowth. J.Biol.Chem. 280, 5646-5650

Commentary: Galione A: F1000Prime Recommendation of [Brailoiu E et al., J Biol Chem 2005, 280(7):5646-50]. In F1000Prime, 12 Jan 2005; DOI: 10.3410/f.1023223.266706. F1000Prime.com/1023223#eval266706

Brailoiu, E., Patel, S. and Dun, N. J. (2003) Modulation of spontaneous transmitter release from the frog neuromuscular junction by interacting intracellular Ca2+ stores: critical role for nicotinic acid-adenine dinucleotide phosphate (NAADP). Biochem.J. 373, 313-318

Commentary: Rutter, G. A. (2003) Calcium signalling: NAADP comes out of the shadows Biochem.J. 373, e3-e4

Patel, S., Robb-Gaspers, L. D., Stellato, K. A., Shon, M. and Thomas, A. P. (1999) Coordination of calcium signalling by endothelial-derived nitric oxide in the intact liver. Nat.Cell Biol. 1, 467-471

Commentary: Charles, A. (1999) Nitric oxide pumps up calcium signalling Nat.Cell Biol. 1, E193-E195 (News and Views)
Commentary: Tordjmann, T., Combettes, L., and Claret, M. (2000) Nitric oxide as a calcium wave accelerator Hepatology 32, 156-157

Page last modified on 03 feb 15 11:28 by Sonja Van Praag (WAMS)