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23 results on '"Du, Chunyun"'

5. The effects of acidosis on the hERG potassium channel

Author

Du, Chunyun

Subjects
547.05383
Abstract

The human ether-a-go-go-related gene (hERG) encodes channels mediating the rapid delayed rectifier K+ current (IKr). IKr participates in cardiac action potential (AP) repolarisation and may also protect the ventricles against premature stimulation. The heart is exposed to acidosis (low pH) in a number of pathological conditions including myocardial ischemia. Extracellular acidosis is known to modulate hERG current (IhERG) function, although a number of aspects of the modulation remain incompletely understood. The aims of this investigation were to establish the effects of acidosis on: (i) IhERG amplitude, kinetics and the response to premature stimulation at mammalian physiological temperature; (ii) the hERG blocking potency of selected anti arrhythmic drugs. Whole-cell patch-clamp recordings of IhERG were made from mammalian cells (CHO or HEK 293) at 37 QC. Lowering external pH from 7.4 to 6.3 reduced the magnitude of IhERG by reducing macroscopic hERG conductance and modulating IhERG kinetics, with positively shifted activation and accelerated deactivation. Results from experiments using an acidic pipette solution showed that the actions of protons occurred from the external surface and not from secondary intracellular acidosis. Experimental and computer simulation work demonstrated that acidosis impairs the protective role of IhERG against premature stimulation. The effects of extracellular acidosis on IhERG kinetics were preserved when the shortened hERG I b isoform was studied, indicating that a full-length N-terminus is not necessary for acidic modulation of hERG channel function. Interestingly, the inhibitory effect of acidosis on IhERG was greater for hERG 1 band hERG lall b than for hERG la. Extracellular acidosis decreased the hERG blocking potency of flecainide, dofetilide and ranolazine, whilst the potency of amiodarone was unaffected. IhERG inactivation was found to be important for ranolazine's inhibitory action and a series of S6 and inner helix residues (Y652, F656, T623, S624 and V625) were identified as contributing to ranolazine binding. I.

Published
2011

16. Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease

Author

Batson, Jennifer, Toop, Hamish D., Redondo, Clara, Babaei-Jadid, Roya, Chaikuad, Apirat, Wearmouth, Stephen F., Gibbons, Brian, Allen, Claire, Tallant, Cynthia, Zhang, Jingxue, Du, Chunyun, Hancox, Jules C., Hawtrey, Tom, Rocha, Joana Pinto da, Griffith, Renate, Knapp, Stefan, Bates, David O., Morris, Jonathan C., Batson, Jennifer, Toop, Hamish D., Redondo, Clara, Babaei-Jadid, Roya, Chaikuad, Apirat, Wearmouth, Stephen F., Gibbons, Brian, Allen, Claire, Tallant, Cynthia, Zhang, Jingxue, Du, Chunyun, Hancox, Jules C., Hawtrey, Tom, Rocha, Joana Pinto da, Griffith, Renate, Knapp, Stefan, Bates, David O., and Morris, Jonathan C.

Abstract

Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity. Treatment with these inhibitors inhibited SRPK1 activity and phosphorylation of serine/arginine splicing factor 1 (SRSF1), resulting in alternative splicing of VEGF-A from pro-angiogenic to antiangiogenic isoforms. This property resulted in potent inhibition of blood vessel growth in models of choroidal angiogenesis in vivo. This work identifies tool compounds for splice isoform selective targeting of pro-angiogenic VEGF, which may lead to new therapeutic strategies for a diversity of diseases where dysfunctional splicing drives disease development.

Published
2017

17. Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease

Author

Batson, Jennifer, primary, Toop, Hamish D., additional, Redondo, Clara, additional, Babaei-Jadidi, Roya, additional, Chaikuad, Apirat, additional, Wearmouth, Stephen F., additional, Gibbons, Brian, additional, Allen, Claire, additional, Tallant, Cynthia, additional, Zhang, Jingxue, additional, Du, Chunyun, additional, Hancox, Jules C., additional, Hawtrey, Tom, additional, Da Rocha, Joana, additional, Griffith, Renate, additional, Knapp, Stefan, additional, Bates, David O., additional, and Morris, Jonathan C., additional

Published
2017
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22. Topical Antiangiogenic SRPK1 Inhibitors Reduce Choroidal Neovascularization in Rodent Models of Exudative AMD

Author

Gammons, Melissa V., primary, Fedorov, Oleg, additional, Ivison, David, additional, Du, Chunyun, additional, Clark, Tamsyn, additional, Hopkins, Claire, additional, Hagiwara, Masatoshi, additional, Dick, Andrew D., additional, Cox, Russell, additional, Harper, Steven J., additional, Hancox, Jules C., additional, Knapp, Stefan, additional, and Bates, David O., additional

Published
2013
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23. Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease

Author

Batson, Jennifer, Toop, Hamish D., Redondo, Clara, Babaei-Jadidi, Roya, Chaikaud, Apirat, Wearmouth, Stephen F., Gibbons, Brian, Allen, Claire, Tallant, Cynthia, Zhang, Jingxue, Du, Chunyun, Hancox, Jules C., Hawtrey, Tom, Da Rocha, Joana, Griffith, Renate, Knapp, Stefan, Bates, David O., Morris, Jonathan C., Batson, Jennifer, Toop, Hamish D., Redondo, Clara, Babaei-Jadidi, Roya, Chaikaud, Apirat, Wearmouth, Stephen F., Gibbons, Brian, Allen, Claire, Tallant, Cynthia, Zhang, Jingxue, Du, Chunyun, Hancox, Jules C., Hawtrey, Tom, Da Rocha, Joana, Griffith, Renate, Knapp, Stefan, Bates, David O., and Morris, Jonathan C.

Abstract

Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity. Treatment with these inhibitors inhibited SRPK1 activity and phosphorylation of serine/arginine splicing factor 1 (SRSF1), resulting in alternative splicing of VEGF-A from pro-angiogenic to antiangiogenic isoforms. This property resulted in potent inhibition of blood vessel growth in models of choroidal angiogenesis in vivo. This work identifies tool compounds for splice isoform selective targeting of pro-angiogenic VEGF, which may lead to new therapeutic strategies for a diversity of diseases where dysfunctional splicing drives disease development.

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