My lab is interested in understanding ion channel function and system modulation in animal physiology and behavior. Our research is centered on the characterization of voltage gated Ca²⁺ channels and their modulatory proteins in cerebellum and hindbrain. We will apply patch clamp measurements in cultured cells and slice preparations, virus mediated infection methods (Sindbis virus), imaging techniques (two photon microscopy, TIRF, FLIM, FRET, FRAP, BiFC) and mouse genetics (transgene expression and homologous recombination) to investigate the following topics:

1. Defining the role of P/Q-type Ca²⁺ channels domains for subcellular targeting, function and animal behavior. Ca²⁺ channels mediate voltage-dependent Ca²⁺ influx in subcellular compartments of neurons, triggering such diverse processes as neurotransmitter release, dendritic action potentials and excitation-transcription coupling. A fundamental question that remains unsolved is how Ca²⁺ channels are targeted to the appropriate cellular compartments especially the presynaptic terminal. This issue is critical to understanding both the basic physiology of neurons as well as several important neurological diseases such as familial hemiplegic migraine (FHM) and spinocerebellar ataxia 6 (SCA6), where mutations in voltage-gated Ca²⁺ channels cause changes in the density of Ca²⁺ channel complexes, alter their biophysical properties and change their potency to interact with intracellular modulating proteins like G proteins and Ca²⁺ channel ancillary subunits. We are in particular excited about investigating the role of the human P/Q-type SCA6 mutation in the living animal. The future goal of this research is to understand the mechanism of the disease process and to develop a cure.
2. Defining the role of G protein modulation and neuronal activity of the serotonergic transmitter system for animal physiology (blood pressure regulation) and behavior (anxiety and depression). The vertebrate serotonergic neurotransmitter system consists of a relatively small number of neurons, which project to the spinal cord and into almost every brain region. This expansive projection system thereby permits serotonergic neurons to modulate important physiological and behavioral functions such as mood, sexual behavior, circadian rhythm and anxiety. We are in particular interested in understanding how the regulation of G protein modulation within the serotonergic system influences the signaling output in the brain. This will ultimately lead to the understanding of mammalian behavior and may accelerate the development of therapeutic treatments for anxiety and depression.

1. Li X, Gutierrez DV, Hanson MG, Han J, Mark MD, Chiel H, Hegemann P, Landmesser LT, Herlitze S. (2005)
   Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin. Proc Natl Acad Sci U S A. 2005 Dec 6; 102(49):17816-17821. 2005/11/23 [aheadofprint].
   
2. Scott MM, Wylie CJ, Lerch JK, Murphy R, Lobur K, Herlitze S, Jiang W, Conlon RA, Strowbridge BW, Deneris ES. (2005)
   A genetic approach to access serotonin neurons for in vivo and in vitro studies. Proc Natl Acad Sci U S A. 2005 Nov 8; 102(45):16472-16477. 2005/10/26 [aheadofprint].
   
3. Li X, Hummer A, Han J, Xie M, Melnik-Martinez K, Moreno RL, Buck M, Mark MD, Herlitze S. (2005)
   G protein beta2 subunit-derived peptides for inhibition and induction of G protein pathways. Examination of voltage-gated Ca2+ and G protein inwardly rectifying K+ channels. J Biol Chem. 2005 Jun 24; 280(25):23945-23959. 2005/04/11 [aheadofprint].
   
4. Kurata HT, Phillips LR, Rose T, Loussouarn G, Herlitze S, Fritzenschaft H, Enkvetchakul D, Nichols CG, Baukrowitz T. (2004)
   Molecular basis of inward rectification: polyamine interaction sites located by combined channel and ligand mutagenesis. J Gen Physiol. 2004 Nov; 124(5):541-554. 2004/10/11 [aheadofprint].
   
5. Herlitze S, Xie M, Han J, Hummer A, Melnik-Martinez KV, Moreno RL, Mark MD. (2003)
   Targeting mechanisms of high voltage-activated Ca2+ channels. J Bioenerg Biomembr. 2003 Dec; 35(6):621-637.
   
6. Hummer A, Delzeith O, Gomez SR, Moreno RL, Mark MD, Herlitze S. (2003)
   Competitive and synergistic interactions of G protein beta(2) and Ca(2+) channel beta(1b) subunits with Ca(v)2.1 channels, revealed by mammalian two-hybrid and fluorescence resonance energy transfer measurements. J Biol Chem. 2003 Dec 5; 278(49):49386-49400. 2003/09/24 [aheadofprint].
   
7. Herlitze S, Zhong H, Scheuer T, Catterall WA. (2001)
   Allosteric modulation of Ca2+ channels by G proteins, voltage-dependent facilitation, protein kinase C, and Ca(v)beta subunits. Proc Natl Acad Sci U S A. 2001 Apr 10; 98(8):4699-4704.
   
8. Mark MD, Wittemann S, Herlitze S. (2000)
   G protein modulation of recombinant P/Q-type calcium channels by regulators of G protein signalling proteins. J Physiol. 2000 Oct 1; 528 Pt 1:65-77.
   
9. Mark MD, Herlitze S. (2000)
   G-protein mediated gating of inward-rectifier K+ channels. Eur J Biochem. 2000 Oct; 267(19):5830-5836.
   
10. Mark MD, Ruppersberg JP, Herlitze S. (2000)
    Regulation of GIRK channel deactivation by Galpha(q) and Galpha(i/o) pathways. Neuropharmacology. 2000 Sep; 39(12):2360-2373.
    
11. Wittemann S, Mark MD, Rettig J, Herlitze S. (2000)
    Synaptic localization and presynaptic function of calcium channel beta 4-subunits in cultured hippocampal neurons. J Biol Chem. 2000 Dec 1; 275(48):37807-37814.
    
12. Herlitze S, Ruppersberg JP, Mark MD. (1999)
    New roles for RGS2, 5 and 8 on the ratio-dependent modulation of recombinant GIRK channels expressed in Xenopus oocytes. J Physiol. 1999 Jun 1; 517 ( Pt 2):341-352.
    
13. Baukrowitz T, Schulte U, Oliver D, Herlitze S, Krauter T, Tucker SJ, Ruppersberg JP, Fakler B. (1998)
    PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science. 1998 Nov 6; 282(5391):1141-1144.
    
14. Herlitze S, Hockerman GH, Scheuer T, Catterall WA. (1997)
    Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel alpha1A subunit. Proc Natl Acad Sci U S A. 1997 Feb 18; 94(4):1512-1516.
    
15. Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, Catterall WA. (1996)
    Modulation of Ca2+ channels by G-protein beta gamma subunits. Nature. 1996 Mar 21; 380(6571):258-262.