Physiology and Biophysics : Graduate Faculty

H. Peter Larsson, Ph.D.

Associate Professor

305-243-1021 (office)

305-243-5931 (fax)

Rosenstiel Medical Science Building 5123

PLarsson@med.miami.edu

Curriculum Vitae

B.S. (Physics) Swiss Institute of Technology (Switzerland), 1989
M.S. (Physics Engineering), Lund University (Sweden), 1989
Ph.D. (Biophysics), University of California, Berkeley, 1994
Postdoctoral Fellow, University of California Berkeley, 1994-1997
Assistant Professor, Karolinska Institute, 1997-2000
Associate Professor, Oregon Health & Science University 2000-2008
Associate Professor, University of Miami, 2008-

Research Interests

Dr. Larsson’s laboratory studies the molecular mechanisms of voltage-gated ion channels and amino acid transporters. Voltage-gated ion channels are proteins spanning the cell membrane of nerve cells. These channels open their ion selective pore in response to changes in the voltage across the cell membrane, allowing ions to flow in or out of the cell. The flow of ions, such as sodium, potassium and calcium, through the voltage-gated ion channels underlie the generation of the nerve signal. The work in Dr Larsson's lab is aimed to understand the molecular mechanisms that open and close these voltage-gated ion channels. Since mutations have been found in voltage-gated ion channels in patients with diseases such as epilepsy, irregular heart rhythms, and periodic paralyses, an understanding of the structure and function of these channels could lead to the development of treatments for a number of disorders.

We have identified the voltage sensor in a number of these voltage-gated ion channels and found that the voltage-sensing mechanism is very conserved among different channel types. However, how the movement of the voltage sensor causes the channel to open its pore is still not understood. While most voltage-gated ion channels are opened by a depolarization of the cell, there is one class of voltage-gated channels that are opened by hyperpolarization: hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels. These channels share many common structural features with ion channels that open by depolarization. One project in the lab is to understand why the hyperpolarization-activated ion channels open with the reverse polarity (i.e. opening at negative potentials) compared to the depolarization-activated channels (opening at positive potentials), even if these two classes of channels share a similar molecular structure. The Larsson lab uses molecular biology, biochemistry, fluorescence, and electrophysiology to measure conformational changes in voltage-gated ion channels, in order to understand the molecular mechanisms underlying the opening of these ion channels.

Another project in the lab is aimed at understanding how glutamate transporters function. Glutamate transporters are membrane-spanning proteins that remove glutamate from the extracellular space around neurons by taking it up into neurons or glial cells. Glutamate is the main neurotransmitter in the Central Nervous System. The removal of glutamate from the synapse, after neurotransmitter release, is essential to maintain a functional communication between neurons and to prevent glutamate to reach neurotoxic levels. The molecular mechanism for the glutamate uptake transport is not very well understood. We are using electrophysiological, fluorescence (e.g. FRET) and electron paramagnetic resonance (EPR) methods to identify conformational changes in glutamate transporters. These measurements will help us to understand the molecular mechanism of how glutamate is taken up into cells.

Recent Publications

Koch, H.P., Kurokawa, T., Okochi, Y., Sasaki, M., Okamura,Y., and Larsson, H.P. Multimeric nature of voltage-gate proton channels (2008), PNAS, 105(26):9111-6.

Koch, H.P., Hubbard, J.M., and Larsson, H.P. Voltage-independent sodium-binding events reported by the 4B-4C loop in the human glutamate transporters EAAT3. (2007) J Biol.Chem. 282(34):24547-53.

Bruening-Wright, A., Elinder, F., and Larsson, H.P. Kinetic relationship between the voltage sensor and the activation gate in spHCN channels. (2007) J. Gen. Phys.130(1):71-81.

Koch, H.P., Brown, R.L., and Larsson, H.P. The glutamate-activated anion conductance in EAATs is gated independently by the individual subunits. (2007) J Neurosci. 27(11):2943-7.

Bruening-Wright, A. and Larsson, H.P. Slow Conformational Changes of the Voltage Sensor during the Mode Shift in HCN Channels. (2007) J. Neurosci. 27:279-278.

Koch, H.P. and Larsson, H.P. Small-scale molecular motions accomplish glutamate uptake in human glutamate transporters. (2005) J Neurosci. 25(7):1730-1736.

Männikkö, R., Pandey, S., Larsson, H.P., and Elinder, F. Hysteresis in the voltage dependence of HCN channels: Conversion between two modes affect pacemaker properties. (2005) J Gen Physiol. 125(3):305-326.

Larsson, H.P., Tzingounis, A.V., Koch, H.P., and Kavanaugh, M.P. Fluorometric measurements of conformational changes in glutamate transporters. (2004) PNAS vol. 101(11), 3951-3956.

Männikkö, R., Elinder, F., and Larsson, H.P. Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages. (2002) Nature vol. 419, 837-841.

Larsson, H.P. and Elinder, F. A Conserved Glutamate is Important for Slow Inactivation in Shaker K+ Channels. (2000) Neuron, vol. 27, 573-583.

Baker, O.S., Larsson, H.P., Mannuzzu, L.M., and Isacoff, E.Y. Three Transmembrane Conformations and Sequence-dependent Displacement of the S4 Domain in Shaker K Channel Gating. (1998) Neuron vol. 20, 1283-1294.

Larsson, H.P., Baker, O.S., Dhillon, D.S., and Isacoff, E.Y. Transmembrane Movement of Shaker K Channel S4. (1996) Neuron 16, 387-397.

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