The long-term goal of our research is to understand how cells maintain intracellular Ca2+ homeostasis in diverse physiological conditions. As a versatile signaling molecule, Ca2+ regulates the proliferation, differentiation, function, aging, and apoptosis of virtually all types of cells. Abnormal calcium homeostasis may cause damage to the cell, and has been implicated in aging and in numerous human diseases, such as Alzheimer's disease and spinocerebellar ataxia. To avoid undesirable effects of Ca2+, all pathways of Ca2+ entry are tightly controlled in the cell. A group of ubiquitously expressed Ca2+ influx channels, termed receptor-operated Ca2+/cation channels (ROCs), are stimulated by G protein-coupled receptors (GPCRs) through Gq/11 proteins and phospholipase C (PLC). Since most GPCRs and ROCs have much higher protein levels in excitable cells including neurons, to maintain the intracellular Ca2+ homeostasis, these cells need to fortify the regulatory machinery of GPCR/ROC by expressing more regulatory molecules. We have previously demonstrated that dCAMTA, a transcription factor responding to the Ca2+ sensor calmodulin, is indispensable for rapid deactivation of the light-stimulated GPCR rhodopsin in the Drosophila eye. dCAMTA belongs to a new family of transcription factors named calmodulin-binding transcription activators (CAMTAs). Interestingly, both human CAMTAs, CAMTA1 and CAMTA2, are highly expressed in the brain. We predict that the calmodulin/CAMTA-stimulated gene expression may fortify the control machinery of GPCR/ROC-mediated Ca2+ entry in neurons, in a long-term feedback manner. To test this hypothesis, we propose to use dCAMTA as model and to take advantage of the fly phototransduction cascade, a typical GPCR/PLC cascade that has been successfully used for the identification of the first ROC channel TRP. In this proposal, we will 1. Test the hypothesis that the dCAMTA target gene dFbxl4 is indispensable for rapid deactivation of rhodopsin;2. Test the hypothesis that dFbxl4 interacts with the myosin III NINAC for rhodopsin deactivation;3. Test the hypothesis that dCAMTA promotes expression of calmodulin to facilitate the deactivation of rhodopsin;4. Test the hypothesis that loss of dCAMTA leads to Ca2+-dependent, vacuolar photoreceptor degeneration in older flies;5. identify the nuclear localization sequences of dCAMTA and human CAMTA1;6. Test the hypothesis that Fbxl4 and/or cam1 are target genes of human CAMTA1.

Public Health Relevance

Defects in calcium homeostasis have been implicated in a variety of human disorders including several neurodegeneration diseases (Alzheimer's disease and spinocerebellar ataxia) and several forms of immunodeficiency The long- term goal of this research is to fully understand how the intracellular Ca2+ homeostasis is maintained in both physiological and pathological conditions and to use this knowledge to facilitate treatment and perhaps prevention of these human diseases. This proposal will study how a new group of transcription factors regulate the Ca2+ homeostasis in a feedback manner.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Velazquez, Jose M
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University of Massachusetts Medical School Worcester
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Luan, Zhuo; Quigley, Caitlin; Li, Hong-Sheng (2015) The putative Na?/Cl?-dependent neurotransmitter/osmolyte transporter inebriated in the Drosophila hindgut is essential for the maintenance of systemic water homeostasis. Sci Rep 5:7993
Luan, Zhuo; Reddig, Keith; Li, Hong-Sheng (2014) Loss of Na(+)/K(+)-ATPase in Drosophila photoreceptors leads to blindness and age-dependent neurodegeneration. Exp Neurol 261:791-801
Chaturvedi, Ratna; Reddig, Keith; Li, Hong-Sheng (2014) Long-distance mechanism of neurotransmitter recycling mediated by glial network facilitates visual function in Drosophila. Proc Natl Acad Sci U S A 111:2812-7
Luan, Zhuo; Li, Hong-Sheng (2012) Inwardly rectifying potassium channels in Drosophila. Sheng Li Xue Bao 64:515-9
Hu, Wen; Wan, Didi; Yu, Xiaoming et al. (2012) Protein Gq modulates termination of phototransduction and prevents retinal degeneration. J Biol Chem 287:13911-8
Cao, Jinguo; Li, Yi; Xia, Wenjing et al. (2011) A Drosophila metallophosphoesterase mediates deglycosylation of rhodopsin. EMBO J 30:3701-13
Venkatachalam, Kartik; Wasserman, David; Wang, Xiaoyue et al. (2010) Dependence on a retinophilin/myosin complex for stability of PKC and INAD and termination of phototransduction. J Neurosci 30:11337-45
Ni, Lina; Guo, Peiyi; Reddig, Keith et al. (2008) Mutation of a TADR protein leads to rhodopsin and Gq-dependent retinal degeneration in Drosophila. J Neurosci 28:13478-87
Han, Junhai; Reddig, Keith; Li, Hong-Sheng (2007) Prolonged G(q) activity triggers fly rhodopsin endocytosis and degradation, and reduces photoreceptor sensitivity. EMBO J 26:4966-73
Gong, Ping; Han, Junhai; Reddig, Keith et al. (2007) A potential dimerization region of dCAMTA is critical for termination of fly visual response. J Biol Chem 282:21253-8

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