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Molecular and Structural Requirements of the Β1l

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Molecular and Structural Requirements of the Β1l MOLECULAR AND STRUCTURAL REQUIREMENTS OF THE 1L-ADRENOCEPTOR Paul Klenowski BBiotech (Hons) Submitted in [partial] fulfilment of the requirements for the degree of Doctor of Philosophy Institute of Health and Biomedical Innovation Faculty of Health Queensland University of Technology [September 2012] Keywords Affinity, agonist, antagonist, 1L-adrenoceptor, 1H-adrenoceptor, 2-adrenoceptor, 3-adrenoceptor, -blocker, (-)-bupranolol, cardiostimulation, cardiovascular, catecholamines, (-)-CGP 12177, (-)-[3H]- CGP 12177, chimera, contractility, crystal structure, cyclic AMP, G-protein coupled receptor, heterologous, human atrial force, human heart failure, (-)-isoprenaline, L-748,337, ligand, low-affinity binding site, L- type Ca2+ channel, molecular modelling, non-conventional partial agonists, noradrenaline, pindolol, positive inotropic effect, potency, radioligand binding, recombinant, site-directed mutagenesis, transmembrane domain i Abstract There are two binding sites on the β1-adrenoceptor (AR), β1H and β1L corresponding to high and low-affinity binding sites respectively, which can be activated to cause cardiostimulation. Some β-blockers typified by (-)-CGP 12177 and (-)-pindolol block β1AR and β2ARs, but also activate β1LARs at higher concentrations than those required to cause blockade. However, in a report by Skeberdis et al., (2008) it was proposed that the positive inotropic effects of (-)-CGP 12177 are mediated through β3ARs. Consequently, experiments were performed using human atrial trabeculae, to investigate whether the β3AR selective antagonist L-748,337 could antagonise the positive inotropic effects of the β3AR agonists SR 58611, BRL 37344 and (-)-CGP 12177. These experiments did not detect inotropic effects of SR 58611 (1 nM-10 M). The positive inotropic effects of BRL 37344 were antagonised by the 1AR and 2AR antagonist nadolol (200 nM) and 2AR antagonist ICI 118,551 (50 nM). Concurrent ICI 118,551 and CGP 20712A (β1AR selective antagonist) addition caused a greater shift of the curve of BRL 37344 than ICI 118,551 alone. Furthermore, the 3AR-selective antagonist L-748,337 (1 M) did not affect the responses to BRL 37344. These results indicate that the effects of BRL 37344 are mediated through 1AR and 2AR but not 3AR. (-)-CGP 12177 (200 nM) caused stable increases in contractile force which were significantly reduced by the addition of (-)-bupranolol (1 M) but not affected by the addition of L-748,337 (1 M, P = 0.001, 1-way ANOVA). The results of trabeculae obtained from 4 patients revealed that L-748,337 did not affect the response to (-)-CGP 12177 (P = 0.12), inconsistent with mediation through 3AR. In contrast, (-)-bupranolol reduced the response by 91 ± 16%, n = 4, P = 0.002, consistent with mediation through 1LAR, as observed before on human atrium (Kaumann et al., 1996a) and recombinant 1AR (Joseph et al., 2004b). Studies have demonstrated that β2AR does not form a corresponding low- affinity binding site (Baker et al., 2002), therefore it was hypothesised that ii heterologous β1- β2AR amino acids are responsible for the formation of β1LAR. This study investigated whether heterologous amino acids of the fifth transmembrane domain (TMDV) of β1AR and β2ARs contribute to β1LAR. β1ARs, β2ARs and mutant β1ARs containing all (β1/β2TMDVAR) or single amino acids of TMDV of the β2AR were prepared and stably expressed in Chinese Hamster Ovary cells. Concentration- effect curves for cyclic AMP accumulation were carried out for (-)-CGP 12177 or (-)-isoprenaline in the absence and presence of (-)-bupranolol. The potencies (pEC50) of (-)-CGP 12177 and affinities (pKB) of (-)-bupranolol versus (-)-CGP 12177 were: Cell Line pEC50 (-)-CGP 12177 n pKB (-)-bupranolol n β2AR 9.10 ± 0.18 14 9.31 ± 0.16 7 β1(V230I)AR 9.08 ± 0.07 10 7.64 ± 0.12 8 β1/β2TMDVAR 8.90 ± 0.10 15 8.06 ± 0.17 8 β1(R222Q)AR 8.10 ± 0.10 6 7.33 ± 0.23 5 β1AR 7.96 ± 0.09 14 7.20 ± 0.16 8 The potency of (-)-CGP 12177 was higher at β2AR than at β1AR, consistent with activation through a low-affinity site at the β1AR (β1LAR). The presence of valine at position 230 in β1AR accounted for the lower potency of (-)-CGP 12177. The affinity of (-)-bupranolol was lower at β1AR compared to β2AR. The presence of valine 230 in β1AR accounted in part for the lower affinity. In conclusion, TMDV and valine 230 of the β1AR contribute in part to the low-affinity binding site of β1AR. iii Table of Contents Keywords ................................................................................................................................................. i Abstract ................................................................................................................................................... ii Table of Contents ................................................................................................................................... iv List of Figures ........................................................................................................................................ vi List of Tables ......................................................................................................................................... ix List of Abbreviations .............................................................................................................................. x Statement of Original Authorship ....................................................................................................... xiii Publications and Conference Abstracts ................................................................................................ xiv Acknowledgements ............................................................................................................................... xv CHAPTER 1: INTRODUCTION ....................................................................................................... 1 CHAPTER 2: LITERATURE REVIEW ........................................................................................... 5 2.1 G-Protein Coupled Receptors ...................................................................................................... 5 2.2 -Adrenoceptors .......................................................................................................................... 6 2.2.1 1AR Gene and Protein Structure ..................................................................................... 7 2.3 Structural Components of the 1AR ............................................................................................ 9 2.3.1 N-Terminus and Extracellular Loops ............................................................................... 9 2.3.2 Transmembrane Domain Regions and 1AR Ligand Binding Pocket ............................ 10 2.3.3 Intracellular Loops and G-Protein Binding .................................................................... 13 2.4 GPCR Signalling and Activation ............................................................................................... 15 2.4.1 1AR Activation ............................................................................................................. 16 2.4.2 1AR Signalling .............................................................................................................. 21 2.5 AR Signalling in the Human Heart .......................................................................................... 23 2.5.1 The Role of1AR in Heart Failure ................................................................................. 27 2.6 1LAR Pharmacology ................................................................................................................. 31 2.6.1 Mechanistic Studies Into the Pharmacology of 1LAR ................................................... 32 2.6.2 The Putative β4-Adrenoceptor: A Working Hypothesis ................................................. 33 2.6.3 Proposal of a Low-Affinity Form of the β1-Adrenoceptor ............................................. 35 2.6.4 Pharmacological Differences Between the Putative β4-Adrenoceptor and Low- Affinity β1-Adrenoceptor ................................................................................................ 37 2.6.5 The Underlying Role of β1-Adrenoceptors in Putative β4-Adrenoceptor Pharmacology ................................................................................................................. 38 2.6.6 Structural Implications of High and Low-Affinity Binding of Non-Conventional Partial Agonists to β1-Adrenoceptors ............................................................................. 39 2.6.7 Functional and Clinical Implication of the β1L-Adrenoceptor ........................................ 41 2.7 Summary and Implications ........................................................................................................ 43 CHAPTER 3: MATERIALS AND METHODS .............................................................................. 45 3.1 Research Design ........................................................................................................................ 45 3.2 materials and Methods ............................................................................................................... 47 3.2.1 General Reagents ............................................................................................................ 47 3.2.2 General Methods ............................................................................................................ 50 3.2.3 Radioligand
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