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Kv4 channels mediate the somatodendritic A-type current (Isa) and are major regulators of neuronal excitability and firing frequency. Kv4.2 channels preferentially associate with two auxiliary subunits, Kv channel-interacting proteins (KChIPs) and dipeptidyl aminopeptidase-like protein 6 (DPP6), which modulate channel voltage-dependent gating and surface expression. Significantly, DPP6 dysfunction has been associated with a myriad of human brain disorders, presenting the Kv4.2 Isa complex as a promising drug target. Here, a variety of approaches were used to gain insights into Kv4.2 and to understand the molecular basis of DPP6 modulation. A series of constructs and expression strategies were investigated to enable mammalian expression of the human Kv4.2-KChIP3-DPP6 complex. In parallel, electrophysiological characterisation of Kv4.2 C-terminal truncation mutants alone and co-assembled with DPP6 revealed the cytoplasmic portion of the channel S6 helix is important for the generation and expression of functional channels, and that the C-terminus regulates Kv4.2 functional expression, but may play a reduced role in channel gating in the presence of DPP6. Further, mutagenesis of cysteine residues C529 and C530 in the C terminus predicted to be S-palmitoylation sites reduced Kv4.2 current amplitudes supporting S palmitoylation of the C-terminus may regulate Kv4.2 surface expression. Finally, a novel study using homology modelling and mutational analysis of the DPP6 transmembrane helix was conducted to investigate key residues involved in its functional coupling with Kv4.2. This revealed two binding regions important for the modulatory effects of DPP6, but not for increased channel trafficking; and highlighted specific DPP6 residues conferring the accelerated Kv4.2 recovery from inactivation, an essential characteristic of the Isa current. Overall, insights have been gained into the structural and functional properties of Kv4.2 and how DPP6 exerts its modulatory effects on the channel, which provide important details on the pathophysiology of human brain disorders associated with mutations in the DPP6 gene and aid the design of novel Kv4.2-selective modulators.

Manufacturing SMEs are suggested to be of continuing importance to economic growth and are a target for regional development policies which have focused on innovation and learning as a primary route to increased corporate (and consequently regional) competitiveness. Despite this policy focus on SMEs there is a limited understanding of how they undertake product development in practice. Firm-level policies are frequently informed by `best practice' models based on large-firm activities, and which may not therefore, be appropriate to SME contexts. The thesis seeks to understand what the process of product development in manufacturing SMEs is, and specifically, how it is managed, how inputs to the process are sourced, and which constraints might limit SMEs in their product development activity. The thesis is the product of an ESRC CASE studentship with the Regional Technology Centre (RTC North) Ltd as the industrial partner. An initial aim of the research was (in line with the Case sponsor's concerns) to identify `good practice' in product development management. As data collection progressed this initial way of understanding firm-level product development practices (as a process which could be reduced to a series of `good practice' management steps) was found to be inadequate. The structure of the thesis reflects this change in understandings. The findings presented in the thesis are based on five case studies and twenty five interviews (utilising qualitative research methods) undertaken at manufacturing SMEs between November 1999 and February 2002. Whilst particular ways of managing the product development process, which approximated to `good practice' recommendations suggested in the literature, did appear to enable some companies to manage their product development processes in more efficient and effective ways, overall, the degree to which firms were able to implement these recommendations was very much contingent on their individual circumstances and characteristics, relating to, for example, the firm's industrial or market sector, the background and specialisms of the company owner or managing director, particular project-specific characteristics relating to the degree of novelty in the project for the developing firm, and the number of technical staff employed in the firm, loosely in relation to the company's overall number of employees. The research suggests significant variety in the SME population, both overall and specifically in relation to approaches to product development. This therefore poses a difficulty for policymakers in designing or implementing a `standard' policy solution. The research draws on the resource or competence-based perspective in order to better understand the unique position of firms in relation to the product development processes, but additionally understands product development as a political and potentially contested arena within the firm. Differences were apparent between how interviewees suggested the process should be managed (in terms of both `best practice' prescriptions but also in terms of `official' company procedures) and how this was done in practice. Managing product development itself appeared to be a learning process, and this suggests that it can become a key company capability. Non-technical problems arising on development projects which related to political or conflict-based issues were largely ignored by managers, and this approach is reflected in current innovation policy support which at a firm level primarily seeks to address technical problems.