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SUMMARY:Calcium channels of vascular remodelling - Prof David J Beech\, In
 st of Membrane &amp\; Systems Biology\, Faculty of Biological Sciences\, U
 niv of Leeds
DTSTART:20110512T150000Z
DTEND:20110512T160000Z
UID:TALK30023@talks.cam.ac.uk
CONTACT:Christian Scheppach
DESCRIPTION:Vascular remodelling in physiology and disease is contributed 
 to significantly by vascular\nsmooth muscle and endothelial cells that hav
 e switched from their quiescent phenotype\nto a phenotype characterised by
  properties such as proliferation\, migration\, secretion\nand invasion. W
 e have sought to understand ion channels in this context\, particularly in
 \nhuman diseased tissues. We find that the switch is associated with chang
 es in ion\nchannels\, which are increasingly appreciated as important for 
 the functional behaviour of\nthese disease-related cells. Striking feature
 s are the de novo expressions of KCa3.1 and\nKV1.3 potassium channels in s
 mooth muscle cells and consequently the opportunity to\ninhibit remodellin
 g by blockers of the channels. An intriguing factor controlling the\npotas
 sium channel gene expression is the repressive transcription factor REST\,
  which is\ndown-regulated during phenotypic switching and neointimal forma
 tion. Concomitant with\ngain of potassium channels is loss of the L-type v
 oltage-dependent calcium channel and\nelevated voltage-independent TRPC1 c
 alcium- and sodium-permeable channel in\nsmooth muscle cells. Antibody tar
 geted to TRPC1 inhibited neointimal formation\,\nsuggesting a hypothesis w
 hereby hyperpolarisation driven by potassium channel activity\nenhances ca
 lcium and sodium entry through TRPC1-containing channels which then\nfacil
 itates calcium-dependent cell cycle activity and gene expression. We have 
 also\nfound roles of ion channels in the migration of vascular cells\, sho
 wing that inhibition of\nTRPC5-containing channels inhibits migration evok
 ed by sphingosine-1-phosphate and\noxidized phospholipids such as 1-palmit
 oyl-2-glutaroyl-phosphatidylcholine. TRPC5\nturns out to have complex poly
 modal regulation including activation by extracellular\nredox protein and 
 specific phospholipids\, contrasting with inhibition by factors that\nprot
 ect against disease such as nitric oxide and resveratrol. We are also find
 ing\nintriguing additional calcium-permeable channels that either suppress
  or enhance\nremodelling. One type of channel is activated by so-called 
 ‘fountain of youth’ steroids\,\nanother by the key growth factor\, PDG
 F. These and other recent findings will be\ndiscussed and placed in the co
 ntext of hypotheses for how remodelling vascular cells\nuse ion channel sy
 stems that may be manipulated for therapeutic benefit.\n\nExample backgrou
 nd references from the lab: Naylor et al (2011) JBC 286\, 5078-5086\;\nChe
 ong et al (2011) Cardiovasc Res 89\, 282-289\; AL-Shawaf et al (2010) Arte
 rio\nThromb Vasc Biol 30\, 1453-1459\; Naylor et al (2010) Circ Res 106\, 
 1507-1515\; Li et al\n(2008) Circ Res 103\, 97-104\; Xu et al (2008) Natur
 e 451\, 69-72\; Kumar et al (2006) Circ\nRes 98\, 557-563\; Cheong et al (
 2005) Mol Cell 20\, 45-52.\n\nFinancial support for the lab is kindly prov
 ided by: Wellcome Trust\, British Heart\nFoundation\, Medical Research Cou
 ncil\, Cancer Research UK\, BBSRC\, AstraZeneca\,\nChina Scholarship Counc
 il.\n\nLab web page: http://www.cardiovascular.leeds.ac.uk/staff/Beech/\n
LOCATION:Hodgkin Huxley Seminar Room\, Physiology Building\, Downing Site
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