The overall goal of my research is to understand how G-proteins modulate ion channels and intracellular signaling pathways and how this modulation in turn determines neuronal network function and behavior. Not easily addressed in the reduced preparations where G-protein signaling is for the most part studied are the two most basic questions: Why are neuronal systems modulated by G-proteins and how is G-protein specificity achieved?
I thus set out to develop the knowledge, tools and strategies to address these questions. We first developed means to visualize dynamically the G-protein modulation in living cells using FRET techniques. Next we developed a non-invasive approach to induce G-protein modulation into channels and neuronal activity into neuronal networks by light using vertebrate rhodopsin and green algae channelrhodopsin (PNAS-2005-102-17816). This indeed, was the first demonstration that a neuronal network can be silenced and/or activated using two different light activated proteins. The light activated GPCRs have been further developed and are currently be used to control cerebellar and serotonergic signaling to gain an understanding of the role of various signaling pathways for motor coordination, motor learning and emotional behavior.
Mark MD, Maejima T, Kuckelsberg D, Yoo JW, Hyde R, Shah V, Gutierrez D, Moreno RL, Kruse W, Noebels J, Herlitze S (2011). Delayed postnatal loss of P/Q type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1A mutations. J Neurosci 31(11):4311-26.
Liu C, Maejima T, Wyler S, Casadeus G, Herlitze S, Deneris ES (2010). Pet-1 is required across different stages of life to regulate serotonergic function. Nature Neurosci 13(10):1190-8.
Han J, Mark MD, Waka S, Rettig J, Herlitze S (2006). RGS2 determines short-term synaptic plasticity in hippocampal neurons via regulation of Gi/o mediated presynaptic Ca2+ channel inhibition. Neuron 51:575-586.
Li X, Gutierrez D, Hanson G, Han J, Mark MD, Chiel H, Hegemann P, Landmesser LT, Herlitze S (2005). Fast non-invasive control of neuronal excitability and network behavior by vertebrate rhodopsin and green algae channelrhodopsin. Proc Natl Acad Sci U S A 102:17816-17821.
Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, Catterall WA (1996). Modulation of Ca2+ channels by G-protein bg subunits. Nature 380:258-262.