Dr Paola Pedarzani
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.
Regulation of G Protein-Coupled Receptor Function by the G Protein-Coupled Receptor Kinase Family
Regulation of signal processing in neurons
The central nervous system regulation of energy homeostasis
Dr Martin Stocker; Prof Dame Linda Partridge; Prof David Gems; Prof Daniel Cutler; Prof Chris Richards; Prof Dominic Withers; Dr Julie Pitcher; Prof Michael Duchen; Dr Rachel Batterham
- Taylor RD, Madsen MG, Krause M, Sampedro-Castañeda M, Stocker M, Pedarzani P (2013). Pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sIAHP in CA1 pyramidal neurons by activating multiple signaling pathways.. Hippocampus, , - . doi:10.1002/hipo.22201
- Gymnopoulos M, Cingolani LA, Pedarzani P, Stocker M (2013). Developmental mapping of small conductance calcium-activated potassium channel expression in the rat nervous system. Journal of Comparative Neurology, , - . doi:10.1002/cne.23466
- Nazzaro C, Greco B, Cerovic M, Baxter P, Rubino T, Trusel M, Parolaro D, Tkatch T, Benfenati F, Pedarzani P, Tonini R (2012). SK channel modulation rescues striatal plasticity and control over habit in cannabinoid tolerance.. Nat Neurosci, 15(2), 284 - 293. doi:10.1038/nn.3022
- Costello DA, Claret M, Al-Qassab H, Plattner F, Irvine EE, Choudhury AI, Giese KP, Withers DJ, Pedarzani P (2012). Brain deletion of insulin receptor substrate 2 disrupts hippocampal synaptic plasticity and metaplasticity.. PLoS One, 7(2), e31124 - . doi:10.1371/journal.pone.0031124
- Fadool DA, Tucker K, Pedarzani P (2011). Mitral cells of the olfactory bulb perform metabolic sensing and are disrupted by obesity at the level of the Kv1.3 ion channel.. PLoS One, 6(9), e24921 - . doi:10.1371/journal.pone.0024921
- Tucker K, Cavallin MA, Jean-Baptiste P, Biju KC, Overton JM, Pedarzani P, Fadool DA (2010). The Olfactory Bulb: A Metabolic Sensor of Brain Insulin and Glucose Concentrations via a Voltage-Gated Potassium Channel.. Results Probl Cell Differ, 52, 147 - 157. doi:10.1007/978-3-642-14426-4_12
- Pedarzani P, Stocker M (2008). Molecular and cellular basis of small--and intermediate-conductance, calcium-activated potassium channel function in the brain.. Cell Mol Life Sci, 65(20), 3196 - 3217. doi:10.1007/s00018-008-8216-x
- Pedarzani P, Cockcroft S, Challiss RAJ (2007). Compartmentalized signalling in neurones. The Journal of Physiology, 584(2), 371 - 372. doi:10.1113/jphysiol.2007.144766
- Strobaek D, Hougaard C, Johansen TH, Sorensen US, Nielsen EO, Nielsen KS, Taylor RD, Pedarzani P, Christophersen P (2006). Inhibitory gating modulation of small conductance Ca2+-activated K+ channels by the synthetic compound (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphtylamine (NS8593) reduces afterhyperpolarizing current in hippocampal CA1 neurons. Molecular Pharmacology, 70(5), 1771 - 1782. doi:10.1124/mol.106.027110
- Pedarzani P, McCutcheon JE, Rogge G, Jensen BS, Christophersen P, Hougaard C, Strobaek D, Stocker M (2005). Specific Enhancement of SK Channel Activity Selectively Potentiates the Afterhyperpolarizing Current IAHP and Modulates the Firing Properties of Hippocampal Pyramidal Neurons.. Journal of Biological Chemistry, 280(50), 41404 - 41411. doi:10.1074/jbc.M509610200
- Stocker M, Hirzel K, D'hoedt D, Pedarzani P (2004). Matching molecules to function: neuronal Ca2+-activated K+ channels and afterhyperpolarizations.. Toxicon, 43(8), 933 - 949. doi:10.1016/j.toxicon.2003.12.009
- Raffaelli G, Saviane C, Mohajerani MH, Pedarzani P, Cherubini E (2004). BK potassium channels control transmitter release at CA3-CA3 synapses in the rat hippocampus.. The Journal of Physiology, 557(1), 147 - 157.
- D'hoedt D, Hirzel K, Pedarzani P, Stocker M (2004). Domain analysis of the calcium-activated potassium channel SK1 from rat brain. Functional expression and toxin sensitivity.. Journal of Biological Chemistry, 279(13), 12088 - 12092.
- Krause M, Offermanns S, Stocker M, Pedarzani P (2002). Functional specificity of G alpha q and G alpha11 in the cholinergic and glutamatergic modulation of potassium currents and excitability in hippocampal neurons. Journal of Neuroscience, 22(3), 666 - 673.
- Pedarzani P, D'hoedt D, Doorty KB, Wadsworth JDF, Joseph JS, Jeyaseelan K, Kini RM, Gadre SV, Sapatnekar SM, Stocker M, Strong PN (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. Journal of Biological Chemistry, 277(48), 46101 - 46109.
- Kulik A, Brockhaus J, Pedarzani P, Ballanyi K (2002). Chemical anoxia activates ATP-sensitive and blocks Ca(2+)-dependent K(+) channels in rat dorsal vagal neurons in situ.. Neuroscience, 110(3), 541 - 554.
- Cingolani LA, Gymnopoulos M, Boccaccio A, Stocker M, Pedarzani P (2002). Developmental regulation of small-conductance Ca2+-activated K+ channel expression and function in rat Purkinje neurons.. J Neurosci, 22(11), 4456 - 4467.
- Pedarzani P, Mosbacher J, Rivard A, Cingolani LA, Oliver D, Stocker M, Adelman JP, Fakler B (2001). Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels. Journal of Biological Chemistry, 276(13), 9762 - 9769. doi:10.1074/jbc.M010001200
- Savic N, Pedarzani P, Sciancalepore M (2001). Medium afterhyperpolarization and firing pattern modulation in interneurons of stratum radiatum in the CA3 hippocampal region.. Journal of Neurophysiology, 85(5), 1986 - 1997.
- Pedarzani P, Kulik A, Muller M, Ballanyi K, Stocker M (2000). Molecular determinants of Ca2+-dependent K+ channel function in rat dorsal vagal neurones.. J Physiol, 527 Pt 2, 283 - 290.
- Krause M, Pedarzani P (2000). A protein phosphatase is involved in the cholinergic suppression of the Ca(2+)-activated K(+) current sI(AHP) in hippocampal pyramidal neurons.. Neuropharmacology, 397(7), 1274 - 1283. doi:10.1016/S0028-3908(99)00227-0
- Stocker M, Pedarzani P (2000). Differential distribution of three Ca(2+)-activated K(+) channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system.. Mol Cell Neurosci, 15(5), 476 - 493. doi:10.1006/mcne.2000.0842
- Stocker M, Krause M, Pedarzani P (1999). An apamin-sensitive Ca2+-activated K+ current in hippocampal pyramidal neurons.. Proc Natl Acad Sci U S A, 96(8), 4662 - 4667.
- Pedarzani P, Krause M, Haug T, Storm JF, Stühmer W (1998). Modulation of the Ca2+-activated K+ current sIAHP by a phosphatase-kinase balance under basal conditions in rat CA1 pyramidal neurons.. J Neurophysiol, 79(6), 3252 - 3256.
- Pedarzani P, Storm JF (1996). Interaction between alpha- and beta-adrenergic receptor agonists modulating the slow Ca(2+)-activated K+ current IAHP in hippocampal neurons.. Eur J Neurosci, 8(10), 2098 - 2110.
- Pedarzani P, Storm JF (1996). Evidence that Ca/calmodulin-dependent protein kinase mediates the modulation of the Ca2+-dependent K+ current, IAHP, by acetylcholine, but not by glutamate, in hippocampal neurons.. Pflugers Arch, 431(5), 723 - 728.
- Pedarzani P, Storm JF (1995). Dopamine modulates the slow Ca(2+)-activated K+ current IAHP via cyclic AMP-dependent protein kinase in hippocampal neurons.. J Neurophysiol, 74(6), 2749 - 2753.
- Pedarzani P, Storm JF (1995). Protein kinase A-independent modulation of ion channels in the brain by cyclic AMP.. Proc Natl Acad Sci U S A, 92(25), 11716 - 11720.
- Pedarzani P, Storm JF (1993). PKA mediates the effects of monoamine transmitters on the K+ current underlying the slow spike frequency adaptation in hippocampal neurons.. Neuron, 11(6), 1023 - 1035.
- Rettig J, Wunder F, Stocker M, Lichtinghagen R, Mastiaux F, Beckh S, Kues W, Pedarzani P, Schröter KH, Ruppersberg JP (1992). Characterization of a Shaw-related potassium channel family in rat brain.. EMBO J, 11(7), 2473 - 2486.
- Tonini R, Ferraro T, Sampedro M, Stocker M, Richards CD, Pedarzani P (). Small conductance Ca2+-activated K+ channels modulate action potential-induced Ca2+ transients in hippocampal neurons.. Journal of Neurophysiology, , - .