To investigate the properties, distribution and function of BK channels (also called maxi-K or slo channels).
To determine the extent to which BK channels serve to limit hyperexcitability, calcium influx, excitotoxicity and cell death in brain disorders such as epilepsy and stroke, in order to provide a basis for assessing the therapeutic potential of pharmacological manipulations of this channel type.
Among the ion channels that regulate neuronal activity, the potassium (K)channels form the most diverse group, playing multiple roles in brain activity and disease. Thus, K channels not only set the resting potential and regulate nerve impulses; they are also essential for preventing pathological hyperactivity, such as epileptic discharges, or the excessive calcium (Ca)influx, exitotoxicity and cell death following ischemic brain injury. The pharmaceutical industry therefore shows considerable interest in K channels. ASME that is in the forefront of developing K channel modulators against brain disorders, is a key participant in this proposal. This project focuses on a particularly prominent and widespread type of Kchannels in the brain, the BK channels (also called maxi-K or sloehannels).
This channel type has a unique set of properties, and can be subject to extensive physiological and pharmacological modulation. In spite of this, little is known about its functional roles. Our goal is to determine the extent to which BK channels serve to limit hyper-excitability, Ca influx, excitotoxicity and cell death in brain disorders such as epilepsy and stroke, in order to provide a basis for pharmacological exploitation of this channel type.
Recently, a series of new tools and methods has been developed: selective toxins, radioligands and modulators, and improved methods for mapping the sub-cellular distribution of ion channels. Already, BK channels have been found both pre- and post-synaptically in a variety of important brain regions, where they are located in strategic positions for dynamic feedback control of Cainflux and transmitter release. Thus, they are also potential regulators of Ca-dependent processes involved in synaptic learning mechanisms, as well as of pathological hyperactivity. We propose collaboration between four European research groups, each in the forefront of its field, to investigate the properties, distribution and functions of neuronal BK channels in the mammalian brain, combining molecular biology, biochemistry, anatomy, electro-physiology, and pharmacological and behavioural studies. Our working hypothesis is that the BK channels act as an "emergency brake", serving to limit neuronal hyperactivity, Ca influx and cell death in epilepsy, stroke and other brain disorders. The project complies with research areas 3.2.3 and 3.1 of the BIOMED 2 work programme.
Funding SchemeCSC - Cost-sharing contracts