Deletion of Connexin45 in Mouse Retinal Neurons Disrupts the Rod/Cone Signaling Pathway between AII Amacrine and ON Cone Bipolar Cells and Leads to Impaired Visual Transmission

Maxeiner, Stephan; Dedek, Karin; Janssen‐Bienhold, Ulrike; Ammermüller, Josef; Brune, Hendrik; Kirsch, Taryn; Pieper, Mario; Degen, Joachim; Krüger, Olaf; Willecke, Klaus; Weiler, Reto

doi:10.1523/jneurosci.3232-04.2005

Cited by 136 publications

(171 citation statements)

References 52 publications

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“…This seems not to be the case, however, and the current state of knowledge suggests that they contain Cx36 on the AII amacrine side and either Cx36 or Cx45 on the bipolar side (Dedek et al, 2006;Han and Massey, 2005;Lin et al, 2005;Maxeiner et al, 2005). It is still unclear, however, how the individual connexons are assembled on the bipolar side, i.e., to which extent there are both homomeric Cx36 and Cx45 connexons and heteromeric Cx36-Cx45 connexons.…”

Section: Connexins Involved In Gap Junctions Of Aii Amacrine Cellsmentioning

confidence: 98%

Electrical synapses between AII amacrine cells in the retina: Function and modulation

Hartveit

Veruki

2012

Brain Research

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Adaptation enables the visual system to operate across a large range of background light intensities. There is evidence that one component of this adaptation is mediated by modulation of gap junctions functioning as electrical synapses, thereby tuning and functionally optimizing specific retinal microcircuits and pathways. The AII amacrine cell is an interneuron found in most mammalian retinas and plays a crucial role for processing visual signals in starlight, twilight and daylight. AII amacrine cells are connected to each other by gap junctions, potentially serving as a substrate for signal averaging and noise reduction, and there is evidence that the strength of electrical coupling is modulated by the level of background light. Whereas there is extensive knowledge concerning the retinal microcircuits that involve the AII amacrine cell, it is less clear which signaling pathways and intracellular transduction mechanisms are involved in modulating the junctional conductance between electrically coupled AII amacrine cells. Here we review the current state of knowledge, with a focus on recent evidence that suggests that the modulatory control involves activity-dependent changes in the phosphorylation of the gap junction channels between AII amacrine cells, potentially linked to their intracellular Ca 2+ dynamics.

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Section: Connexins Involved In Gap Junctions Of Aii Amacrine Cellsmentioning

confidence: 98%

Electrical synapses between AII amacrine cells in the retina: Function and modulation

Hartveit

Veruki

2012

Brain Research

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“…The embryonic lethality can be circumvented by α myosin heavy chain promoter-Cre-mediated deletion (Agah et al 1997) of Cx45 in conditional Cx45-deficient mice (Maxeiner et al 2005; S. Maxeiner and K. Willecke, unpublished observations). These mice may therefore be useful for further study of the function of Cx45 in the mammalian heart.…”

Section: Alterations Of Cardiac Conduction In Cx-deficient Micementioning

confidence: 99%

Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Kreuzberg

Willecke

Bukauskas

2006

Trends in Cardiovascular Medicine

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In mouse heart, four connexins (Cxs), Cx30.2, Cx40, Cx43, and Cx45, form gap junction (GJ) channels for electric and metabolic cell-to-cell signaling. Extent and pattern of Cx isoform expression together with cytoarchitecture and excitability of cells determine the velocity of excitation spread in different regions of the heart. In the SA node, cell-cell coupling is mediated by Cx30.2 and Cx45, which form lowconductance (approximately 9 and 32 pS, respectively) GJ channels. In contrast, the working cardiomyocytes of atria and ventricles express mainly Cx40 and Cx43, which form GJ channels of high conductance (approximately 180 and 115 pS, respectively) that facilitate the fast conduction necessary for efficient mechanical contraction. In the AV node, cell-cell coupling is mediated by abundantly expressed Cx30.2 and Cx45 and Cx40, which is expressed to a lesser extent. Cx30.2 and Cx45 may determine higher intercellular resistance and slower conduction in the SA-and AV-nodal regions than in the ventricular conduction system or the atrial and ventricular working myocardium. Cx30.2 and its putative human ortholog, Cx31.9, under physiologic conditions form unapposed hemichannels in nonjunctional plasma membrane; these hemichannels have a conductance of approximately 20 pS and are permeable to cationic dyes up to approximately 400 Da in molecular mass. Genetic ablation of Cxs confirmed that Cx40 and Cx43 are important in determining the high conduction velocities in atria and ventricles, whereas the deletion of the Cx30.2 complementary DNA led to accelerated conduction in the AV node and reduced the Wenckebach period. We suggest that these effects are caused by (1) a dominant-negative effect of Cx30.2 on junctional conductance via formation of low-conductance homotypic and heterotypic GJ channels, and (2) open Cx30.2 hemichannels in non-junctional membranes, which shorten the space constant and depolarize the excitable membrane.In the mammalian heart, gap junction (GJ) channels mediate electric and metabolic communication between cardiac myocytes, thereby allowing cardiac impulse propagation and coordinated contraction of the chambers. Gap junction channels, which connect the cytosplasms of two adjacent cells and enable the diffusion of molecules up to approximately 1 kDa molecular mass, are composed of two hemichannels or connexons (Kumar and Gilula 1996). Each hemichannel consists of six connexin (Cx) protein subunits that are encoded by a multigene family comprising at least 20 members in the mouse and human genome (Söhl and Willecke 2004). Different Cxs coexpressed in the same tissue can form homotypic (same Cx isotype in both hemichannels), heterotypic (two Cx isotypes form cell-cell

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“…In the inner retina, AII amacrine cells of the rod pathway are coupled to other AII amacrine cells via Cx36 gap junctions (Feigenspan et al, 2001;Mills et al, 2001) but they also make heterotypic Cx36/Cx45 gap junctions with ON cone bipolar cells (Han & Massey, 2005;Lin et al, 2005;Maxeiner et al, 2005;Dedek et al, 2006). This pathway has been shown to be essential for the transmission of dark-adapted rod signals through the retinal network (Deans et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Screening of gap junction antagonists on dye coupling in the rabbit retina

2007

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Many cell types in the retina are coupled via gap junctions and so there is a pressing need for a potent and reversible gap junction antagonist. We screened a series of potential gap junction antagonists by evaluating their effects on dye coupling in the network of A-type horizontal cells. We evaluated the following compounds: meclofenamic acid (MFA), mefloquine, 2-aminoethyldiphenyl borate (2-APB), 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid (18-β-GA), retinoic acid, flufenamic acid, niflumic acid, and carbenoxolone. The efficacy of each drug was determined by measuring the diffusion coefficient for Neurobiotin (Mills & Massey, 1998). MFA, 18-β-GA, 2-APB and mefloquine were the most effective antagonists, completely eliminating A-type horizontal cell coupling at a concentration of 200 μM. Niflumic acid, flufenamic acid, and carbenoxolone were less potent. Additionally, carbenoxolone was difficult to wash out and also may be harmful, as the retina became opaque and swollen. MFA, 18-β-GA, 2-APB and mefloquine also blocked coupling in Btype horizontal cells and AII amacrine cells. Because these cell types express different connexins, this suggests that the antagonists were relatively non-selective across several different types of gap junction. It should be emphasized that MFA was water-soluble and its effects on dye coupling were easily reversible. In contrast, the other gap junction antagonists, except carbenoxolone, required DMSO to make stock solutions and were difficult to wash out of the preparation at the doses required to block coupling in A-type HCs. The combination of potency, water solubility and reversibility suggest that MFA may be a useful compound to manipulate gap junction coupling.

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Deletion of Connexin45 in Mouse Retinal Neurons Disrupts the Rod/Cone Signaling Pathway between AII Amacrine and ON Cone Bipolar Cells and Leads to Impaired Visual Transmission

Cited by 136 publications

References 52 publications

Electrical synapses between AII amacrine cells in the retina: Function and modulation

Electrical synapses between AII amacrine cells in the retina: Function and modulation

Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Screening of gap junction antagonists on dye coupling in the rabbit retina

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