Knockout of GARPs and the β-subunit of the rod cGMP-gated channel disrupts disk morphogenesis and rod outer segment structural integrity
| Autor: | Shanta Sarfare, Gordon L. Fain, Timothy W. Kraft, Youwen Zhang, Robert S. Molday, Laurie L. Molday, Michael L. Woodruff, Steven J. Pittler |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Protein subunit
Optic Disk Optic disk Morphogenesis Cyclic Nucleotide-Gated Cation Channels Down-Regulation Nerve Tissue Proteins Receptors Cell Surface Biology Mice Homomeric Animals Receptor Vision Ocular Mice Knockout Transporter Rod Cell Outer Segment Anatomy Cell Biology Cell biology Mice Inbred C57BL Guanylate Cyclase ATP-Binding Cassette Transporters Erratum Photic Stimulation Visual phototransduction Research Article |
| Popis: | Ion flow into the rod photoreceptor outer segment (ROS) is regulated by a member of the cyclic-nucleotide-gated cation-channel family; this channel consists of two subunit types, alpha and beta. In the rod cells, the Cngb1 locus encodes the channel beta-subunit and two related glutamic-acid-rich proteins (GARPs). Despite intensive research, it is still unclear why the beta-subunit and GARPs are coexpressed and what function these proteins serve. We hypothesized a role for the proteins in the maintenance of ROS structural integrity. To test this hypothesis, we created a Cngb1 5'-knockout photoreceptor null (Cngb1-X1). Morphologically, ROSs were shorter and, in most rods that were examined, some disks were misaligned, misshapen and abnormally elongated at periods when stratification was still apparent and degeneration was limited. Additionally, a marked reduction in the level of channel alpha-subunit, guanylate cyclase I (GC1) and ATP-binding cassette transporter (ABCA4) was observed without affecting levels of other ROS proteins, consistent with a requirement for the beta-subunit in channel assembly or targeting of select proteins to ROS. Remarkably, phototransduction still occurred when only trace levels of homomeric alpha-subunit channels were present, although rod sensitivity and response amplitude were both substantially reduced. Our results demonstrate that the beta-subunit and GARPs are necessary not only to maintain ROS structural integrity but also for normal disk morphogenesis, and that the beta-subunit is required for normal light sensitivity of the rods. |
| Databáze: | OpenAIRE |
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