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Originally published as Genetics Published Articles Ahead of Print on November 1, 2004.
Genetics, Vol. 169, 737-750, February 2005, Copyright © 2005
doi:10.1534/genetics.104.031930
Analysis of Conditional Paralytic Mutants in Drosophila Sarco-Endoplasmic Reticulum Calcium ATPase Reveals Novel Mechanisms for Regulating Membrane Excitability
S. Sanyal*,
C. Consoulas
,
H. Kuromi
,
A. Basole
,1,
L. Mukai*,
Y. Kidokoro,
K. S. Krishnan,** and
M. Ramaswami*,2
* MCB Department, Life Sciences South, University of Arizona, Tucson, Arizona 85721
Department of Experimental Physiology, Medical School, University of Athens, 11527 Athens, Greece
Institute for Behavioral Sciences, Gunma University School of Medicine, 3-39-22 Showa-machi, Maebashi, Japan
Department of Biological Sciences, Tata Institute of Fundamental Research, Colaba, Mumbai 400005, India
** National Center for Biological Sciences, Bangalore 560 065, India
2 Corresponding author: Department of Molecular and Cellular Biology, 1007 E. Lowell St., Life Sciences South, Box 210106, University of Arizona, Tucson, AZ 85721.
E-mail: mani{at}u.arizona.edu
Individual contributions made by different calcium release and sequestration mechanisms to various aspects of excitable cell physiology are incompletely understood. SERCA, a sarco-endoplasmic reticulum calcium ATPase, being the main agent for calcium uptake into the ER, plays a central role in this process. By isolation and extensive characterization of conditional mutations in the Drosophila SERCA gene, we describe novel roles of this key protein in neuromuscular physiology and enable a genetic analysis of SERCA function. At motor nerve terminals, SERCA inhibition retards calcium sequestration and reduces the amplitude of evoked excitatory junctional currents. This suggests a direct contribution of store-derived calcium in determining the quantal content of evoked release. Conditional paralysis of SERCA mutants is also marked by prolonged neural activity-driven muscle contraction, thus reflecting the phylogenetically conserved role of SERCA in terminating contraction. Further analysis of ionic currents from mutants uncovers SERCA-dependent mechanisms regulating voltage-gated calcium channels and calcium-activated potassium channels that together control muscle excitability. Finally, our identification of dominant loss-of-function mutations in SERCA indicates novel intra- and intermolecular interactions for SERCA in vivo, overlooked by current structural models.
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