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The Journal of Neuroscience, January 17, 2007, 27(3):604-615; doi:10.1523/JNEUROSCI.4099-06.2007

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Cellular/Molecular
In Vivo Identification and Manipulation of the Ca²⁺ Selectivity Filter in the Drosophila Transient Receptor Potential Channel

Che H. Liu,^1 * Tao Wang,^2 * Marten Postma,¹ Alexander G. Obukhov,³ Craig Montell,² and Roger C. Hardie¹

¹Department of Physiology Development and Neuroscience, Cambridge University, Cambridge CB2 3DY, United Kingdom, ²Departments of Biological Chemistry and Neuroscience, Center for Sensory Biology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and ³Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indianapolis 46202

Correspondence should be addressed to Roger C. Hardie, Department of Physiology Development and Neuroscience, Cambridge University, Downing Street, Cambridge CB2 3DY, UK. Email: rch14{at}cam.ac.uk

Null mutations in the transient receptor potential (trp) gene eliminate the major, Ca²⁺-selective component of the light-sensitive conductance in Drosophila photoreceptors. Although it is the prototypical member of the TRP ion channel superfamily, conclusive evidence that TRP is a pore-forming channel subunit in vivo is lacking. We show here that mutating a specific acidic residue (Asp⁶²¹) in the putative pore virtually eliminated Ca²⁺ permeation in vivo and altered other biophysical properties of the native TRP conductance. The results identify Asp⁶²¹ as a critical residue of the TRP Ca²⁺ selectivity filter, provide the first rigorous demonstration that a TRP protein is a pore-forming subunit in any native system, and point to the likely location of the pore in mammalian canonical TRP channels. The specific elimination of Ca²⁺ permeation in TRP also provided a unique opportunity to address the roles of Ca²⁺ influx in vivo. We found that Asp⁶²¹ mutations profoundly affected several key aspects of the light response and caused light-dependent retinal degeneration.

Key words: photoreceptor; pore; calcium channel; permeability; retinal degeneration; TRP channels; TRPC

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Received Sept. 19, 2006; revised Dec. 8, 2006; accepted Dec. 8, 2006.

Correspondence should be addressed to Roger C. Hardie, Department of Physiology Development and Neuroscience, Cambridge University, Downing Street, Cambridge CB2 3DY, UK. Email: rch14{at}cam.ac.uk

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