title: Adenosine and dopamine receptors coregulate photoreceptor coupling via gap junction phosphorylation in mouse retina.
abstract: Gap junctions in retinal photoreceptors suppress voltage noise and facilitate input of rod signals into the cone pathway during mesopic vision. These synapses are highly plastic and regulated by light and circadian clocks. Recent studies have revealed an important role for connexin36 (Cx36) phosphorylation by protein kinase A (PKA) in regulating cell-cell coupling. Dopamine is a light-adaptive signal in the retina, causing uncoupling of photoreceptors via D4 receptors (D4R), which inhibit adenylyl cyclase (AC) and reduce PKA activity. We hypothesized that adenosine, with its extracellular levels increasing in darkness, may serve as a dark signal to coregulate photoreceptor coupling through modulation of gap junction phosphorylation. Both D4R and A2a receptor (A2aR) mRNAs were present in photoreceptors, inner nuclear layer neurons, and ganglion cells in C57BL/6 mouse retina, and showed cyclic expression with partially overlapping rhythms. Pharmacologically activating A2aR or inhibiting D4R in light-adapted daytime retina increased photoreceptor coupling. Cx36 among photoreceptor terminals, representing predominantly rod-cone gap junctions but possibly including some rod-rod and cone-cone gap junctions, was phosphorylated in a PKA-dependent manner by the same treatments. Conversely, inhibiting A2aR or activating D4R in daytime dark-adapted retina decreased Cx36 phosphorylation with similar PKA dependence. A2a-deficient mouse retina showed defective regulation of photoreceptor gap junction phosphorylation, fairly regular dopamine release, and moderately downregulated expression of D4R and AC type 1 mRNA. We conclude that adenosine and dopamine coregulate photoreceptor coupling through opposite action on the PKA pathway and Cx36 phosphorylation. In addition, loss of the A2aR hampered D4R gene expression and function.
authors: Richard S. Ruiz, MD, Department of Ophthalmology and Visual Science, The University of Texas Medical School, Houston, Texas 77030, USA.
authors: Hongyan
authors: H
authors: Li
authors: Zhijing
authors: Z
authors: Zhang
authors: Michael R
authors: MR
authors: Blackburn
authors: Steven W
authors: SW
authors: Wang
authors: Christophe P
authors: CP
authors: Ribelayga
authors: John
authors: J
authors: O'Brien
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D017630:Connexins / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003623:Dark Adaptation / Q000502:physiology; D017629:Gap Junctions / Q000378:metabolism / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D043683:Receptors, Adenosine A2 / Q000235:genetics / Q000502:physiology; D011954:Receptors, Dopamine / Q000235:genetics / Q000502:physiology*; D050638:Receptors, Dopamine D4 / Q000096:biosynthesis / Q000235:genetics; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000502:physiology*; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology*; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology*; D000097004:Gap Junction delta-2 Protein
chemical_list: D000262:Adenylyl Cyclases; D017630:Connexins; D017868:Cyclic AMP-Dependent Protein Kinases; D043683:Receptors, Adenosine A2; D011954:Receptors, Dopamine; D050638:Receptors, Dopamine D4; D018047:Receptors, Purinergic P1; D000097004:Gap Junction delta-2 Protein