Academic Background

Neuronal regulation of membrane receptor signaling

Our lab is interested in neuronal signaling events triggered by membrane receptors and the regulation mechanisms of receptor signaling.  Our current researches are focused on a G-protein coupled receptor (GPCR): the fly light receptor rhodopsin.

    GPCRs are the largest family of receptors on the cell membrane.  They mediate transmembrane signaling of numerous neurotransmitters, hormones, cytokines and sensory stimuli.   Through heterotrimeric G proteins and downstream second messengers such as IP₃/Ca²⁺ and cAMP, GPCRs alter cell membrane potential, control neuronal secretion and regulate cell proliferation and degeneration.  To fine-tune the signaling and prevent excitotoxicity-mediated neuronal damage or degeneration, the cells control the GPCR activity through various regulatory molecules including arrestins and GPCR kinases.  The phosphorylation and binding to arrestin uncouple GPCR from the G protein, a process termed deactivation or desensitization of receptor.  In addition, prolonged activation of GPCR causes endocytosis and downregulation of the receptor protein, and leads to long-term desensitization of the cell to extracellular stimuli.

    Most investigations on the regulation of GPCR were carried out in cultured cells; however, using fly rhodopsin as a genetic model, we are identifying in vivo mechanisms of GPCR regulation in intact photoreceptor neurons.  Upon light stimulation, rhodopsin activates a G_q protein to stimulate phospholipase C, which opens TRP family Ca²⁺/cation channels to depolarize the photoreceptor neuron.  To ensure rapid termination of visual response at the end of stimulation, rhodopsin needs to be deactivated promptly after activating a G_q molecule.  A visual arrestin Arr2 plays a pivotal role in the deactivation of rhodopsin.  Recently we have revealed another pathway of rhodopsin regulation: a fly calmodulin-binding transcription activator (dCAMTA) promotes expression of an F-box and leucine-rich repeat protein dFbxl4 to potentiate deactivation of rhodopsin.  Interestingly, in addition to terminating the light response, the Arr2- and dCAMTA/dFbxl4-mediated rhodopsin deactivations are required to maintain the photoreceptor sensitivity through controlling a G_q-mediated rhodopsin endocytic pathway.  

    Using a combination of molecular and cell biological, electrophysiological and genetic approaches, we are currently isolating and characterizing additional fly mutants that are defective in the control of rhodopsin activity and/or endocytosis.   Some isolated mutants have slow dynamics of visual transduction, while some others undergo severe retinal degeneration due to abnormal rhodopsin signaling.  We have identified the affected genes in several mutants, and found they all have  mammalian homologs highly expressed in the brain. 

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