John Spudich, PhD

Areas of Interest

Research Interests

Research Information

Microbial Rhodopsins: Diversity, Mechanisms, and Optogenetic Applications in Basic and Translational Research

My primary interest is in microbial sensory rhodopsins: their molecular mechanisms and applications as molecular tools for research and gene therapy. After discovery of the first microbial sensory rhodopsin, a phototaxis receptor in an archaeal prokaryote, our subsequent work revealed homologous photosensors to be widespread among both prokaryotic and eukaryotic microorganisms. In particular, we identified sensory rhodopsin homologs in green algae that mediate phototaxis by light-induced membrane depolarization. The photo depolarization is due to light-gated cation conduction by the photosensors, accordingly named channel rhodopsins. Over the years we have implemented photochemistry, structural biology, and biophysical methods to elucidate atomic structure/function relationships in sensory rhodopsin activation, and developed methods for studying their function in animal cells, including neurons and other excitable cells, and in purified systems. Our current research is focused on the light-gated channel activity of channel rhodopsins. In addition to their interest from a basic biology perspective, channel rhodopsins have been the driving force for the technology of optogenetics.

Optogenetics is based on genetic targeting of microbial rhodopsins to defined populations of neurons, enabling use of light to control the targeted neurons’ firing without affecting other neurons in the tissue. Elegant work of neuroscientists has made optogenetics a transformative technology for research on neural circuitry. Because of the temporal and spatial precision provided by using light to activate and silence neuron firing, optogenetics has revolutionized the study of brain circuitry, e.g. learning and memory, the neural determinants of emotions such as pleasure and fear, and the basis of neurological diseases such as epilepsy, Parkinson’s disease, autism, anxiety and depression, and chronic pain. Clinical trials are currently underway using neuron-activating channel rhodopsins in gene-therapy to treat human retinal degeneration diseases causing blindness. The combination of inhibitor and activator optogenetic tools would enhance vision restoration gene-therapy since human vision entails an interplay of photo inhibition and photoactivation of neural pathways. However, until recently, only cation-conducting channel rhodopsins(CCRs) were known, and only weak tools were available for neural inhibition. Our recent discovery of potent neuron-inhibiting natural light-gated anion(physiologically chloride) channels (ACRs) provides new opportunities for neural inhibition for research and clinical use.

临床光遗传学必然始于神经元激活的视紫红蛋白，因为没有有效的神经元抑制剂。我们的实验室（Govorunova等人的Science2015）发现天然视紫红质阴离子通道，通过光门控氯化物电导率有效地沉默神经元，为基因治疗开辟了道路，以解决需要抑制过多神经射击的疾病。实际上，神经元多动在集中涉及多种神经系统疾病的原因或主要症状，例如癫痫，帕金森氏病，自闭症，耳鸣，偏头痛以及慢性和术后神经性疼痛。ACR还可以对心脏功能进行光学控制，以进行研究和潜在的治疗。beplay苹果手机能用吗例如，心脏作用电位的光学缩短可能使心脏病的治疗（如长QT综合征）受益。我们的实验室目前正在专注于了解阴离子通道的分子机制，并为它们设计用于光遗传学疗法。In addition to pursuing my research interests, I am active as an elected Fellow of the American Academy of Arts and Sciences, one of the country’s oldest learned societies and independent policy research centers, and currently serve as President of the International Union of Photobiology, whose mission is to advance research on the roles of light in biology and on photomedicine, including clinical optogenetics, light-therapy for seasonal depression, DNA photo-damage and carcinogenesis, and photodynamic therapy (PDT) for non-surgical cancer treatment.

Selected Publications

Govorunova EG, Sineshchekov OA, Janz R, Liu X, Spudich JL. 2015.Natural Light-gated Anion Channels: A Family of Microbial Rhodopsins for Advanced Optogenetics. Science. 349:647-650.

Sineshchekov OA, Li H, Govorunova EG, Spudich JL. 2016. Photochemical Reaction Cycle Transitions During Anion Channelrhodopsin Gating. Proc Natl Acad Sci USA. 113:E1993-2000.

Govorunova EG, Sineshchekov OA, Li H, Spudich JL. 2017. Microbial Rhodopsins: Diversity, Mechanisms, and Optogenetic Applications. Annu Rev Biochem. 86:845- 872.