Mark Von Zastrow, MD, PhD

Linking Cell Signaling and Membrane Traffic

Chemical signaling between neurons is mediated by specific membrane-embedded receptors, which also mediate the actions of many therapeutic and abused drugs. Signaling receptors are often targeted to defined microdomains of the plasma membrane, such as synaptic specializations. Receptor targeting is critical for appropriate localization, integration and processing of neural signals. Many signaling receptors are regulated by membrane trafficking, which refers to the movement of receptors from one membrane domain to another via vesicular carriers. Receptor trafficking is critical to the regulation of neural signaling and to certain aspects of signal dissemination.

Our laboratory studies mechanisms that mediate and regulate targeting and trafficking of various neural signaling receptors, and we are investigating the physiological functions of specific receptor trafficking mechanisms. We have a major interest in G protein-coupled receptors (GPCRs), the largest family of neural signaling receptors which represent ~1% of transcripts encoded by the human genome and are targets of the majority of therapeutic drugs currently in clinical use. We have focused on opioid neuropeptide receptors because these GPCRs have extremely interesting cell biological properties, which we believe are important to understanding the physiological effects of addictive opiate drugs.

We have observed that distinct GPCRs, even those that are identical in other properties, can differ profoundly in their membrane trafficking. Differences in the membrane trafficking pathways followed by specific GPCRs have major functional consequences to cellular signal transduction, and we are presently studying sorting mechanisms that determine the specificity of receptor trafficking. We are also investigating how non-peptide opiate drugs (such as morphine) differ from endogenously produced neuropeptides (such as endorphins and enkephalins) in their effects on opioid receptor trafficking, and we are investigating the significance of these differences to the analgesic and addictive properties of opiates.

We are interested in the membrane trafficking of ligand-gated ion channels, an important class of neural signaling receptors which mediate rapid synaptic neurotransmission. Both AMPA and NMDA -type glutamate receptors are targeted to postsynaptic specializations of excitatory synapses but follow different membrane trafficking pathways, both for their regulated insertion to and removal from the plasma membrane. We have been particularly interested in endocytic mechanisms that remove glutamate receptors from the plasma membrane and, in collaboration with Roger Nicoll's group, have explored how regulated endocytosis specifically of AMPA -type glutamate receptors modulates synaptic plasticity in hippocampal pyramidal neurons.

Recently we have become interested in how membrane trafficking mechanisms integrate distinct signals in the same neuron. We have observed a previously unanticipated link between neurotrophin signaling (via receptor tyrosine kinases) and trafficking of G protein-coupled opioid neuropeptide receptors through the biosynthetic pathway. This pathway mediates the formation of an intracellular 'reserve' pool of opioid receptors, packaged into what appears to be a novel population of vesicles, which are rapidly inserted to the neuronal plasma membrane in response to electrical stimulation.

Many of our studies are conducted using mammalian cell culture preparations and apply a variety of biochemical and molecular biological methods to elucidate specific mechanisms of receptor membrane trafficking. We are adapting and refining newer gene expression and cellular imaging methods to investigate regulated trafficking of opioid receptors in intact neural tissue, where it is feasible to investigate the effects of receptor trafficking on the regulation of neural circuits. We are also working to develop improved methods for investigating functional effects of specific receptor trafficking mechanisms on whole-animal physiology and behavior.

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