Noradrenergic signaling has important functions in the central nervous system (CNS) with respect to emotion, learning and memory. Activation of β- adrenergic receptors (β ARs) stimulates protein kinase A via Gs-protein, adenylyl cyclase, and cAMP. Synaptic β←2 -adrenergic receptors, targets of the neurotransmitter norephinephrin, are associated with the GluA1 subunit of AMPA-type glutamate receptors, which mediate most excitatory synaptic transmission in mammalian CNS. PKA-mediated phosphorylation of GluA1 on Ser845 is important for GluA1 surface expression, activity induced postsynaptic accumulation, and synaptic plasticity. Postsynaptic localization of PKA is mediated by a major scaffolding protein `A kinase anchor protein 5 (AKAP5)'. AKAP5 associates with AMPA receptors via SAP97 and PSD95. We have two strains of AKAP5 mutant mice: AKAP5 knockout and AKAP5 D36. AKAP5 KO mice have a complete loss of AKAP5 gene expression. D36 mice miss the last 36 residues (PKA binding site) of AKAP5 but without affecting other interactions. These mutant mice provide us with appropriate in vivo models for studying the functional roles of AKAP5. We compared the functional and physical association of β2AR and AMPA receptors among wild type, AKAP5 KO, and AKAP5 D36 mice. Although AKAP5 was not necessary for the assembly of the β2AR / GluA1 complex, we found that AKAP5 anchored PKA activity was required for full β2AR stimulation-induced GluA1 Ser845 phosphorylation. Recording and analysis of field EPSPs (fEPSPs) of CA1 pyramidal neurons with brief bath perfusion of the β2AR agonist isoproterenol indicated a role of AKAP5 anchored PKA in the regulation of postsynaptic AMPAR responses by norephinephrin. Moreover, we observed a delayed extinction of contextual fear memory in AKAP5 D36 mice, which suggests the involvement of AKAP5 anchored PKA in memory formation and modification.

Flies are a widely distributed pest insect that poses a significant threat to food security. Flight is essential for the dispersal of the adult flies to find new food sources and ideal breeding spots. The supply of metabolic fuel to power the flight muscles of insects is regulated by adipokinetic hormones (AKHs). The fruit fly, Drosophila melanogaster, the flesh fly, Sarcophaga crassipalpis, and the oriental fruit fly, Bactrocera dorsalis all have the same AKH that is present in the blowfly, Phormia terraenovae; this AKH has the code-name Phote-HrTH. Binding of the AKH to the extracellular binding site of a G protein-coupled receptor causes its activation. In this thesis, the structure of Phote-HrTH in SDS micelle solution was determined using NMR restrained molecular dynamics. The peptide was found to bind to the micelle and be reasonably rigid, with an S 2 order parameter of 0.96. The translated protein sequence of the AKH receptor from the fruit fly, Drosophila melanogaster, the flesh fly, Sarcophaga crassipalpis, and the oriental fruit fly, Bactrocera dorsalis were used to construct two models for each receptor: Drome-AKHR, Sarcr-AKHR, and Bacdo-AKHR. It is proposed that these two models represent the active and inactive state of the receptor. The models based on the crystal structure of the β-2 adrenergic receptor were found to bind Phote-HrTH with a predicted binding free energy of –107 kJ mol–1 for Drome-AKHR, –102 kJ mol–1 for Sarcr-AKHR and –102 kJ mol–1 for Bacdo-AKHR. Under molecular dynamics simulation, in a POPC membrane, the β-2AR receptor-like complexes transformed to rhodopsin-like. The identification and characterisation of the ligand-binding site of each receptor provide novel information on ligand-receptor interactions, which could lead to the development of species-specific control substances to use discriminately against these pest flies.