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Title: β-adrenoceptor/protein kinase A modulation of rabbit cardiac Na+-Ca2+ exchanger and cystic fibrosis transmembrane conductance regulator
Author: Barman , Palash Pratim
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2013
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The Na2+-Ca2+ Exchanger (NCX), all important Ca2+ handling plasmalemmal protein, is expressed widely in cardiac tissues and plays important roles in physiological and pathophysiological cardiac function . A key aim of this study was to determine whether or not B-adrenoceptor/PKA stimulation modulates NCX current (lNCX), measured as Ni2+ sensitive current, independent of potential contamination from a PKA-activated CI current (lCIPKA), encoded by the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Pharmacological effects of a 'selective' CTFR blocker, GyH-101 were also tested. Additional work was also conducted on human atrial INCX and NCX expression. Methods: Rabbit ventricular and atrial and human atrial myocytes were used in whole-cell patch-clamp experiments at 37°C. Selective conditions for NCX and CI currents were used as appropriate. NCX protein was measured by Western Blotting. Results and conclusions: Under NCX•selective recording conditions 10 mM Ni2+ blocked isoprenaline activated current, but the Nil+• sensitive ventricular INcx activated by forskolin was similar to that in control. In rabbit atrial tissues, which lack ICLPKA, forskolin did not increase the Ni2-•sensitive current component. External but not internal Ni 21 inhibited lc1PKA, with a sub• millimolar IC50, when this was activated by isoprenaline but not forskolin suggestive of a Nil+ action upstream to adenylyl cyclase, likely directly on the B1• adrenoceptor. Thus, the apparent increase rabbit ventricular INt:x with isoprenaline in NCX recording conditions is likely to be attributable to overlapping Ni2+•sensitivc IctPKA, rather than INCX activation by B-adrenoceptor/PKA stimulation. The CFTR inhibitor GlyH•-1Ol produced voltage• dependent inhibition of cardiac IC1PKA, but additionally also inhibited I and IKI . Consequently this compound is not entirely CFTR•selective in respect of cardiac electrophysiology. Human atrial INt:x density and its current voltage relationship were very similar to those of rabbit atrial myocytes. In the human atrial samples examined, there was no significant difference in NCX protein expression between patients in sinus rhythm and those in chronic atrial fibrillation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available