Research Departments & Organizations
Research in our laboratory is aimed at understanding the nature of the biochemical changes that occur in neurons and that result in prolonged changes in the behavior of an animal or in its ability to detect specific patterns of sensory inputs. It is known that alterations of the intrinsic electrical excitability of specific neurons are the key feature of such events, and that these are caused by the short-term and long-term regulation of proteins termed ion channels. Our laboratory has isolated the genes for multiple ion channels, and is studying both how these channels function to in the normal nervous system, and how human mutations in these channels give rise to several neurological conditions that produce severe intellectual disability.
Specialized Terms: Neuroscience; Learning and memory; Ion channels
Extensive Research Description
Our laboratory has investigates the role of potassium channels, as well as other classes of ion channels, in the short-term and long-term regulation of neuronal excitability. Our group was the first to demonstrate directly, using purified enzymes, that excitability of neurons is regulated by cyclic AMP-dependent protein kinase, protein kinase C and tyrosine phosphatases. As part of this work we isolated the genes for over fourteen novel ion channels and were the first to identify the “two-pore” family of potassium channels. Among the channels that our group cloned and characterized are Kv3.1b channel, which is required for high-frequency firing in many neurons and the Slack and Slick genes that underlie Na+-activated K+ channels. Our work was the first to show directly that rapid changes in the phosphorylation state of ion channels and in the synthesis of new channels occur in vivo in response to changes in an animal’s environment. Most recently, we have found that the Slack protein interacts with the Fragile X Mental Retardation Protein FMRP and that human mutations in Slack produce very severe epilepsy and developmental delay. This is now a major focus of our laboratory.
De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy.
Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, Chen H, Kronengold J, Abhyankar A, Cilio R, Nitschke P, Kaminska A, Boddaert N, Casanova JL, Desguerre I, Munnich A, Dulac O, Kaczmarek LK, Colleaux L, Nabbout R. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nature Genetics 2012, 44:1255-9. 2012
Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack.
Brown MR, Kronengold J, Gazula VR, Chen Y, Strumbos JG, Sigworth FJ, Navaratnam D, Kaczmarek LK. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nature Neuroscience 2010, 13:819-21. 2010
Non-conducting functions of voltage-gated ion channels.
Kaczmarek LK. Non-conducting functions of voltage-gated ion channels. Nature Reviews. Neuroscience 2006, 7:761-71. 2006
Acoustic environment determines phosphorylation state of the Kv3.1 potassium channel in auditory neurons.
Song P, Yang Y, Barnes-Davies M, Bhattacharjee A, Hamann M, Forsythe ID, Oliver DL, Kaczmarek LK. Acoustic environment determines phosphorylation state of the Kv3.1 potassium channel in auditory neurons. Nature Neuroscience 2005, 8:1335-42. 2005
Use of optical biosensors to detect modulation of Slack potassium channels by G protein-coupled receptors.
Fleming MR, Kaczmarek LK. Use of optical biosensors to detect modulation of Slack potassium channels by G protein-coupled receptors. Journal Of Receptor And Signal Transduction Research 2009, 29:173-81. 2009
The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels.
Chen H, Kronengold J, Yan Y, Gazula VR, Brown MR, Ma L, Ferreira G, Yang Y, Bhattacharjee A, Sigworth FJ, Salkoff L, Kaczmarek LK. The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels. The Journal Of Neuroscience : The Official Journal Of The Society For Neuroscience 2009, 29:5654-65. 2009
Na+-mediated coupling between AMPA receptors and KNa channels shapes synaptic transmission.
Nanou E, Kyriakatos A, Bhattacharjee A, Kaczmarek LK, Paratcha G, El Manira A. Na+-mediated coupling between AMPA receptors and KNa channels shapes synaptic transmission. Proceedings Of The National Academy Of Sciences Of The United States Of America 2008, 105:20941-6. 2008