Ion-regulatory proreins in neuronal development and communication

Brain function is critically dependent on the ionic homeostasis in both the extra- and intracellular compartment. The regulation of brain extracellular ionic composition mainly relies on active transport at blood brain and at blood cerebrospinal fluid interfaces whereas intracellular ion regulation is based on plasmalemmal transporters of neurons and glia. In addition, the latter mechanisms can generate physiologically as well as pathophysiologically significant extracellular ion transients. In this work I have studied molecular mechanisms and development of ion regulation and how these factors alter neuronal excitability and affect synaptic and non-synaptic transmission with a particular emphasis on intracellular pH and chloride (Cl-) regulation. Why is the regulation of acid-base equivalents (H+ and HCO3-) and Cl- of such interest and importance? First of all, GABAA-receptors are permeable to both HCO3- and Cl-. In the adult mammalian central nervous system (CNS) fast postsynaptic inhibition relies on GABAA-receptor mediated transmission. Today, excitatory effects of GABAA-receptors, both in mature neurons and during the early development, have been recognized and the significance of the dual actions of GABA on neuronal communication has become an interesting field of research. The transmembrane gradients of Cl- and HCO3- determine the reversal potential of GABAA-receptor mediated postsynaptic potentials and hence, the function of pH and Cl- regulatory proteins have profound consequences on GABAergic signaling and neuronal excitability. Secondly, perturbations in pH can cause a variety of changes in cellular function, many of them resulting from the interaction of protons with ionizable side chains of proteins. pH-mediated alterations of protein conformation in e.g. ion channels, transporters, and enzymes can powerfully modulate neurotransmission. In the context of pH homeostasis, the enzyme carbonic anhydrase (CA) needs to be taken into account in parallel with ion transporters: for CO2/HCO3- buffering to act in a fast manner, CO2 (de)hydration must be catalyzed by this enzyme. The acid-base equivalents that serve as substrates in the CO2 dehydration-hydration reaction are also engaged in many carrier and channel mediated ion movements. In such processes, CA activity is in key position to modulate transmembrane solute fluxes and their consequences. The bicarbonate transporters (BTs; SLC4) and the electroneutral cation-chloride cotransporters (CCCs; SLC12) belong the to large gene family of solute carriers (SLCs). In my work I have studied the physiological roles of the K+-Cl- cotransporter KCC2 (Slc12a5) and the Na+-driven Cl--HCO3- exchanger NCBE (Slc4a10) and the roles of these two ion transporters in the modualtion of neuronal communication and excitability in the rodent hippocampus. I have also examined the cellular localization and molecular basis of intracellular CA that has been shown to be essential for the generation of prolonged GABAergic excitation in the mature hippocampus. The results in my Thesis provide direct evidence for the view that the postnatal up-regulation of KCC2 accounts for the developmental shift from depolarizing to hyperpolarizing postsynaptic EGABA-A responses in rat hippocampal pyramidal neurons. The results also indicate that after KCC2 expression the developmental onset of excitatory GABAergic transmission upon intense GABAA-receptor stimulation depend on the expression of intrapyramidal CA, identified as the CA isoform VII. Studies on mice with targeted Slc4a10 gene disruption revealed an important role for NCBE in neuronal pH regulation and in pH-dependent modulation of neuronal excitability. Furthermore, this ion transporter is involved in the basolateral Na+ and HCO3- uptake in choroid plexus epithelial cells, and is thus likely to contribute to cerebrospinal fluid production.

From Creative Ideas to New Emerging Ventures: Entrepreneurial Processes among Finnish Design Entrepreneurs

This study focuses on self-employed industrial designers and how they emerge new venture ideas. More specifically, this study strives to determine what design entrepreneurs do when they create new venture ideas, how venture ideas are nurtured into being, and how the processes are organized to bring such ideas to the market in the given industrial context. In contemporary times when the concern for the creative class is peaking, the research and business communities need more insight of the kind that this study provides, namely how professionals may contribute to their entrepreneurial processes and other agents’ business processes. On the one hand, the interviews underlying this study suggest that design entrepreneurs may act as reactive service providers who are appointed by producers or marketing parties to generate product-related ideas on their behalf. On the other hand, the interviews suggest that proactive behaviour that aims on generating own venture ideas, may force design entrepreneurs to take considerable responsibility in organizing their entrepreneurial processes. Another option is that they strive to bring venture ideas to the market in collaboration, or by passing these to other agents’ product development processes. Design entrepreneurs’ venture ideas typically emerge from design related starting points and observations. Product developers are mainly engaged with creating their own ideas, whereas service providers refer mainly to the development of other agents’ venture ideas. In contrast with design entrepreneurs, external actors commonly emphasize customer demand as their primary source for new venture ideas, as well as development of these in close interaction with available means of production and marketing. Consequently, design entrepreneurs need to address market demand since without sales their venture ideas may as well be classified as art. In case, they want to experiment with creative ideas, then there should be another source of income to support this typically uncertain and extensive process. Currently, it appears like a lot of good venture ideas and resources are being wasted, when venture ideas do not suite available production or business procedures. Sufficient communication between design entrepreneurs and other agents would assist all parties in developing production efficient and distributable venture ideas. Overall, the findings suggest that design entrepreneurs are often involved simultaneously in several processes that aim at emerging new product related ventures. Consequently, design entrepreneurship is conceptualized in this study as a dual process. This implies that design entrepreneurs can simultaneously be in charge of their entrepreneurial processes, as they operate as resources in other agents’ business processes. The interconnection between activities and agents suggests that these kinds of processes tend to be both complex and multifaceted to their nature.