Leonard Konrad Kaczmarek PhD

Professor of Pharmacology and of Cellular and Molecular Physiology

Research Interests

Neuroscience; Learning and memory; Ion channels

Research Summary

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.

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.

Selected Publications

  • Barcia, G., Fleming, M.R, Deligniere, A., Gazula. V.-R., Brown, M.R., Longouet, M., Chen, H., Kronengold, J., Abhyankar, A., Kaminska, A., Boddaert, N., Casanova, J.-L., Desguerre, I., Munnich, A., Dulac, O., Kaczmarek, L.K., Colleaux, L and Nabbout, R. De novo gain of function KCNT1 channel mutations cause developmental arrest and seizures in malignant migrating partial seizures of infancy, Nature Genetics, 44: 1255-1259, 2012. PMCID: PMC 3687547
  • Brown, M.R., Kronengold, J., Gazula, V.-R., Chen, Y., Strumbos, J.G., Sigworth, F.J., Navaratnam, D. and Kaczmarek, L.K. The fragile X mental retardation protein controls gating of the sodium-activated potassium channel, Slack, Nature Neuroscience, 13: 819–821, 2010. PMCID: PMC 2893252
  • Kaczmarek LK. Non-conducting functions of ion channels. Nature Rev Neurosci, 7:761-771, 2006.
  • Song P, Yang Y, Barnes-Davies M, Bhattacharjee A, Hamann M, Forsythe ID, Oliver DL, Kaczmarek LK. Acoustic stimulation rapidly alters intrinsic excitability of auditory neurons. Nature Neurosci, 8:1335-1342, 2005.
  • Fleming MR, Kaczmarek LK. Use of optical biosensors to detect modulation of Slack potassium channels by G protein-coupled receptors. J Recept Signal Transduct Res, 29(3-4):173-81, 2009.
  • 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. J Neurosci, 29(17):5654-65, 2009.
  • 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. Proc Natl Acad Sci USA, 105(52):20941-6, Epub 2008 Dec 18.

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