Roth Lab Research

Chemical-Genetics: in this line of research we have pioneered the use of directed molecular evolution to create GPCRs which are suitable for remotely controlling cellular signaling. Using a variety of mouse genetic approaches (e.g. Cre-mediated recombination; Tet-inducible systems; BAC-transgenic) we are able to control neuronal firing and non-neuronal signaling in real-time in awake, freely moving animals (see Armbruster et al, PNAS 2007; Conklin et al, Nature Methods, 2008; Alexander et al, Neuron 2009; Guettier et al, PNAS 2009; Dong et al, Nature Protocols 2010).

Figure 1:

This technology has afforded the scientific community the opportunity to discover how cell-type specific modulation of signaling is translated into behavioral and non-behavioral outcomes. Ongoing projects are to use this technology to deconstruct the neuronal requirements for simple and complex behaviors, particularly as they relate to schizophrenia and drug abuse.

Chemical Biology and the Receptorome: We have pioneered the approach of massively-parallel physical screening of the GPCR-ome. Our approach differs in that we screen, in a parallel fashion, entire families of receptors simultaneously to discover molecular targets of biologically important molecules (peptides, drugs, natural products). This work is facilitated by the NIMH Psychoactive Drug Screening Program which is housed in the Rothlab.	Figure 2: Massively parallel physical screening of receptorome
Using this approach we have: Discovered the Κ-opioid receptor as the sole molecular target of salvinorin A-the active ingredient of the natural hallucinogen Salvia divinorum (Roth et al, PNAS, 2002). Ongoing projects are to discover the molecular and neurobiological underpinnings of salvinorin A's hallucinogenic actions.
Figure 3: Large-scale screening of human cloned GPCRs reveals Salvinorin A is selective for KOR	Discovered the 5-HT2B receptor as being responsible for drug-induced valvular heart disease (Roth, NEJM, 2007). Ongoing projects are to exploit serotonin receptor pharmacology for psychiatric and obesity-related drug discovery efforts. Together with Brian Shoichet's lab at UCSF used this platform for the near druggable-genome-wide discovery of new molecular targets for approved drugs (Keiser et al, Nature, 2009; Keiser et al, Nature Biotech 2007). Ongoing projects are focused on using this technology to de-orphanize the remaining orphan GPCRs in the genome (~150) and to uncover the hidden pharmacology of known medications.
Serotonin receptor neurobiology: Since 1984, my lab has studied serotonin (5-hydroxytryptamine; 5-HT) and its receptors. Recently we have been focused on targeting and trafficking of 5-HT2-family receptors (Elphick et al, Science, 2004; Scheffler et al, PNAS 2006; Abbas et al, J Neurosci 2009; Magalhaes et al,Nature Neurosci, 2010). Ongoing projects are directed to using mouse genetics to delineate the roles of accessory proteins and post-translational modifications in 5-HT receptor actions.