Molecular and cellular basis of ion channel function in central nervous system neurones
Dr Paola Pedarzani
|Reader in Cellular Neurophysiology|
|Tel: +44 (0)20 7679 7744|
|Paola Pedarzani ... biography|
Ion channels and the regulation of membrane excitability and firing properties of neurones. Ion channels are membrane proteins that control cell permeability to specific ions. They underlie the excitability of neurones and are responsible for signal generation and transmission in the nervous system. The type, properties, number, and specific cell location of ion channels determine the signalling properties of neurones, and the regulation of ion channel activity contributes to complex processes, such as learning and memory. Research in my laboratory focuses on the molecular and cellular basis of ion channel function in central nervous system neurones. Potassium channels are by far the largest and most diverse ion channel family. Over 100 different subunits of distinct types of K+ channels have been identified to date, and the list is still growing. They show different sensitivities to voltage and/or intracellular messengers, have different kinetic and pharmacological properties, and present distinct expression patterns in different tissues. The wide range of K+ channel properties reflects the broad spectrum of cellular functions that they serve, including control of membrane excitability and synaptic efficacy, of heart beat, of sensory processes, and of secretion. One of the major challenges is to understand the functional meaning of this variety of K+ channels.
Molecular determinants of K+ channel function in the brain
Our work has been particularly focusing on Ca2+-activated K+ channels. These channels are activated by submicromolar concentrations of intracellular Ca2+ and generate so-called afterhyperpolarizations (AHP) following single or multiple action potentials. Important functions of the AHP are to limit the number of action potentials and to slow down the firing frequency of neurones during sustained stimulations, a phenomenon known as "spike frequency adaptation". Since neurons use frequency to encode information, changes in the AHP will strongly affect signal processing. In collaboration with Dr. M. Stocker's group at the Wellcome Laboratory for Molecular Pharmacology (UCL), we investigate the molecular makeup of native Ca2+-activated K+ channels, whether channels with different subunit compositions have distinct functions, and how their functional specificity is generated in various neuronal types.
Neuromodulation: mechanisms and impact on signal processing in neurones
Spike frequency adaptation can be shut down by a number of neurotransmitters in the brain. Noradrenaline and other monoamines, for example, are diffusely released when the brain commands arousal or attention, and cause phosphorylation of some Ca2+-activated K+ channels or associated proteins, leading to a reduction in their activity, and therefore in spike frequency adaptation. As a result, neurones are more excitable and can follow inputs more faithfully. This neuromodulatory effect can be regarded as a molecular correlate of paying attention. We are interested in determining the spatial organization, dynamics and interactions of the receptor - II messenger - target systems that are responsible for elaborating specific neuronal responses, such as changes in the firing pattern or oscillatory behaviour of the neurones. Our aim is to elucidate the specific role and integrating properties in the spatial and temporal domains of classic and newly identified signal transduction components and ion channels.
- D. Strobaek, C. Hougaard, T. H. Johansen, U. S. Sorensen, E. O. Nielsen, K. S. Nielsen, R. D. Taylor, P. Pedarzani & P. Christophersen (2006) Inhibitory gating modulation of small conductance Ca2+-activated K+ cby the synthetic compound (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) reduces afterhyperpolarizing current in hippocampal CA1 neurons. Mol. Pharmacol., 70: 1771-1782 link
- P. Pedarzani, J. E. McCutcheon, G. Rogge, B. S. Jensen, P. Christophersen, C. Hougaard, D. Strobaek & M. Stocker (2005) Specific enhancement of SK channel activity selectively potentiates the afterhyperpolarizing current IAHP and modulates the firing properties of hippocampal pyramidal neurons. J. Biol. Chem., 280: 41404-41404-41411 link
- M. Stocker, K. Hirzel, D. D'hoedt & P. Pedarzani. (2004) Matching molecules to function: Neuronal Ca2+-activated K+ channels and afterhyperpolari-zations. Toxicon, 43: 933-949 (2004) REVIEW link
- D. D'hoedt, K. Hirzel, P. Pedarzani & M. Stocker. (2004) Domain analysis of the calcium-activated potassium channel SK1 from rat brain: Functional expression and toxin sensitivity. J. Biol. Chem., 279: 12088-12092 link
- G. Raffaelli, C. Saviane, M. H. Mohajerani, P. Pedarzani & E. Cherubini. (2004) BK channels control transmitter release at CA3-CA3 synapses in the rat hippocampus. J. Physiol., 557: 147-157. link
- P. Pedarzani, D. D'hoedt, K.B. Doorty, J.D.F. Wadsworth, J.S. Joseph, K. Jeyaseelan, R.M. Kini, S.V. Gadre, S.M. Sapatnekar, M. Stocker & P.N. Strong. (2002) Tamapin, a venom peptide from the Indian red scorpion (Mesobuthus tamulus) that targets small conductance Ca2+-activated K+ channels and afterhyperpolarization currents in central neurons. J. Biol. Chem., 277: 46101-46109 link
- L.A. Cingolani, M. Gymnopoulos, A. Boccaccio, M. Stocker & P. Pedarzani (2002) Developmental regulation of small conductance Ca2+-activated K+ channel expression and function in rat Purkinje neurons. Journal of Neuroscience, 22: 4456-4467 link
- M. Krause, S. Offermanns, M. Stocker & P. Pedarzani (2002) Functional specificity of G-alpha-q and G-alpha-11 in the cholinergic and glutamatergic modulation of potassium currents and excitability in hippocampal neurons. Journal of Neuroscience, 22: 666-673 link
- P. Pedarzani, J. Mosbacher, A. Rivard, L. A. Cingolani, D. Oliver, M. Stocker, J. P. Adelman & B. (2001) Fakler Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. J. Biol. Chem. 276: 9762-9769 link
- P. Pedarzani, A. Kulik, M. Müller, K. Ballanyi & M. Stocker (2000) Molecular determinants of Ca2+-dependent K+ channel function in rat dorsal vagal neurones. J. Physiol. 527.2: 283-290 (2000). link