Dopamine-stimulated dephosphorylation of connexin 36 mediates AII amacrine cell uncoupling.
Gap junction proteins form the substrate for electrical coupling between neurons. These electrical synapses are widespread in the CNS and serve a variety of important functions. In the retina, connexin 36 (Cx36) gap junctions couple AII amacrine cells and are a requisite component of the high-sensitivity rod photoreceptor pathway. AII amacrine cell coupling strength is dynamically regulated by background light intensity, and uncoupling is thought to be mediated by dopamine signaling via D(1)-like receptors. One proposed mechanism for this uncoupling involves dopamine-stimulated phosphorylation of Cx36 at regulatory sites, mediated by protein kinase A. Here we provide evidence against this hypothesis and demonstrate a direct relationship between Cx36 phosphorylation and AII amacrine cell coupling strength. Dopamine receptor-driven uncoupling of the AII network results from protein kinase A activation of protein phosphatase 2A and subsequent dephosphorylation of Cx36. Protein phosphatase 1 activity negatively regulates this pathway. We also find that Cx36 gap junctions can exist in widely different phosphorylation states within a single neuron, implying that coupling is controlled at the level of individual gap junctions by locally assembled signaling complexes. This kind of synapse-by-synapse plasticity allows for precise control of neuronal coupling, as well as cell-type-specific responses dependent on the identity of the signaling complexes assembled.
Kothmann
W Wade
WW
Richard S. Ruiz Department of Ophthalmology, University of Texas Medical School at Houston, Houston, Texas 77030, USA. Wade.Kothmann@gmail.com
Massey
Stephen C
SC
O'Brien
John
J
D025042:Amacrine Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D017630:Connexins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D014785:Vision, Ocular / Q000187:drug effects / Q000502:physiology; D000097004:Gap Junction delta-2 Protein
D017630:Connexins; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D000097004:Gap Junction delta-2 Protein