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Dana Specht, Shu-Biao Wu, Paul Turner, Peter Dearden, Frank Koentgen, Uwe Wolfrum, Marion Maw, Johann Helmut Brandstätter, Susanne tom Dieck; Effects of Presynaptic Mutations on a Postsynaptic Cacna1s Calcium Channel Colocalized with mGluR6 at Mouse Photoreceptor Ribbon Synapses. Invest. Ophthalmol. Vis. Sci. 2009;50(2):505-515. doi: 10.1167/iovs.08-2758.
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purpose. Photoreceptor ribbon synapses translate light-dependent changes of membrane potential into graded transmitter release via L-type voltage-dependent calcium channel (VDCC) activity. Functional abnormalities (e.g., a reduced electroretinogram b-wave), arising from mutations of presynaptic proteins, such as Bassoon and the VDCCα1 subunit Cacna1f, have been shown to altered transmitter release. L-type VDCCα1 subtype expression in wild-type and mutant mice was examined, to investigate the underlying pathologic mechanism.
methods. Two antisera against Cacna1f, and a Cacna1f mouse mutant (Cacna1fΔEx14-17) were generated. Immunocytochemistry for L-type VDCCα1 subunits and additional synaptic marker proteins was performed in wild-type, BassoonΔEx4-5 and Cacna1fΔEx14-17 mice.
results. Active zone staining at photoreceptor ribbon synapses with a panα1 antibody colocalized with staining for Cacna1f in wild-type mouse retina. Similarly, in the BassoonΔEx4-5 mouse, residual mislocalized staining for panα1 and Cacna1f showed colocalization. Unlike the presynaptic location of Cacna1f and panα1 antibody staining, the skeletal muscle VDCCα1 subunit Cacna1s was present postsynaptically at ON-bipolar cell dendrites, where it colocalized with metabotropic glutamate receptor 6 (mGluR6). Surprisingly, Cacna1s labeling was severely downregulated in the BassoonΔEx4-5 and Cacna1fΔEx14-17 mutants. Subsequent analyses revealed severely reduced ON-bipolar cell dendritic expression of the sarcoplasmic reticulum Ca2+ ATPase Serca2 in both mouse mutants and of mGluR6 in the Cacna1fΔEx14-17 mutant.
conclusions. Presynaptic mutations leading to reduced photoreceptor-to-bipolar cell signaling are associated with disturbances in protein expression within postsynaptic dendrites. Moreover, detection of Cacna1s and Serca2 in ON-bipolar cell dendrites in wild-type animals suggests a putative role in regulation of postsynaptic Ca2+ flux.
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