Changes in intracellular Ca2+ concentration control a myriad of physiological processes including muscle contraction, secretion, mitosis, channel gating, chemotaxis and stomatal pore closure. During the past 15 years two techniques have revolutionised the study of cell physiology: measurement of Ca2+ concentrations using ratiometric, Ca2+-specific fluorescent indicators such as fura-2; and the rapid increase in concentration of cellular substrates such as ATP, cGMP, etc. from a biologically inert or """"""""caged"""""""" form by flash-photolysis techniques. The objective of this proposal is use rapid photochemical control of divalent cation levels to characterise the mechanism and regulation of cellular physiological processes. Ca2+ -specific photolabile chelators will be developed and used to manipulate intracellular Ca2+ concentrations independently of other effectors, such as Mg2+, ATP, GTP, etc. so that the regulatory roles that these species have on Ca2+-dependent cell physiology can be defined. Additionally, a new, ultra-fast caged IP3 will be synthesised. This key second messenger is implicated in the control of Ca2+ concentration in many cell types. The basis of this proposal is a new Ca2+-specific photolabile chelator called DMNPE-4, which has been recently synthesized. The new probes will be used to study the kinetics and regulation of secretory events in neuroendocrine cells; of contraction in cardiac muscle and the kinetics of Ca2+ release in the cerrebellum because Ca2+ is the key intracellular second messenger in these systems. Many of these processes are disturbed in pathological states. Before an adequate description of these disease states can be given, a more complete understanding of non-disease states should be accomplished. The proposed studies will contribute to a greater understanding of the normal functioning of these processes.
| Passlick, Stefan; Ellis-Davies, Graham C R (2018) Comparative one- and two-photon uncaging of MNI-glutamate and MNI-kainate on hippocampal CA1 neurons. J Neurosci Methods 293:321-328 |
| Passlick, Stefan; Richers, Matthew T; Ellis-Davies, Graham C R (2018) Thermodynamically Stable, Photoreversible Pharmacology in Neurons with One- and Two-Photon Excitation. Angew Chem Int Ed Engl 57:12554-12557 |
| Richers, Matthew T; Tran, Dinh Du; Wachtveitl, Josef et al. (2018) Coumarin-diene photoswitches for rapid and efficient isomerization with visible light. Chem Commun (Camb) 54:4983-4986 |
| Agarwal, Hitesh K; Zhai, Shenyu; Surmeier, D James et al. (2017) Intracellular Uncaging of cGMP with Blue Light. ACS Chem Neurosci 8:2139-2144 |
| Passlick, Stefan; Kramer, Paul F; Richers, Matthew T et al. (2017) Two-color, one-photon uncaging of glutamate and GABA. PLoS One 12:e0187732 |
| Richers, Matthew T; Amatrudo, Joseph M; Olson, Jeremy P et al. (2017) Cloaked Caged Compounds: Chemical Probes for Two-Photon Optoneurobiology. Angew Chem Int Ed Engl 56:193-197 |
| Howarth, Clare; Sutherland, Brad; Choi, Hyun B et al. (2017) A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain. J Neurosci 37:2403-2414 |
| Agarwal, Hitesh K; Janicek, Radoslav; Chi, San-Hui et al. (2016) Calcium Uncaging with Visible Light. J Am Chem Soc 138:3687-93 |
| Sajo, Mari; Ellis-Davies, Graham; Morishita, Hirofumi (2016) Lynx1 Limits Dendritic Spine Turnover in the Adult Visual Cortex. J Neurosci 36:9472-8 |
| Kantevari, Srinivas; Passlick, Stefan; Kwon, Hyung-Bae et al. (2016) Development of Anionically Decorated Caged Neurotransmitters: In Vitro Comparison of 7-Nitroindolinyl- and 2-(p-Phenyl-o-nitrophenyl)propyl-Based Photochemical Probes. Chembiochem 17:953-61 |
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