scholarly journals Asymmetry of an intracellular scaffold at vertebrate electrical synapses

2017 ◽  
Author(s):  
Audrey J Marsh ◽  
Jennifer Carlisle Michel ◽  
Anisha P Adke ◽  
Emily L Heckman ◽  
Adam C Miller
Keyword(s):  
Gap Junction ◽  
Synapse Formation ◽  
Neural Circuit ◽  
Electrical Synapse ◽  
Electrical Synapses ◽  
Gap Junction Channels ◽  
Junction Protein ◽  
Chemical Synapses ◽  
And Function

AbstractNeuronal synaptic connections are electrical or chemical and together are essential to dynamically defining neural circuit function. While chemical synapses are well known for their biochemical complexity, electrical synapses are often viewed as comprised solely of neuronal gap junction channels that allow direct ionic and metabolic communication. However, associated with the gap junction channels are structures observed by electron microscopy called the Electrical Synapse Density (ESD). The ESD has been suggested to be critical for the formation and function of the electrical synapse, yet the biochemical makeup of these structures is poorly understood. Here we find that electrical synapse formation in vivo requires an intracellular scaffold called Tight Junction Protein 1b (Tjp1b). Tjp1b is localized to electrical synapses where it is required for the stabilization of the gap junction channels and for electrical synapse function. Strikingly, we find that Tjp1b protein localizes and functions asymmetrically, exclusively on the postsynaptic side of the synapse. Our findings support a novel model in which there is molecular asymmetry at the level of the intracellular scaffold that is required for building the electrical synapse. ESD molecular asymmetries may be a fundamental motif of all nervous systems and could support functional asymmetry at the electrical synapse.

scholarly journals Trafficking of gap junction channels at a vertebrate electrical synapse in vivo

2012 ◽  
Vol 109 (9) ◽  
pp. E573-E582 ◽  
Author(s):  
C. E. Flores ◽  
S. Nannapaneni ◽  
K. G. V. Davidson ◽  
T. Yasumura ◽  
M. V. L. Bennett ◽  
...  
Keyword(s):  
Gap Junction ◽  
Electrical Synapse ◽  
Gap Junction Channels

scholarly journals cAMP controls a trafficking mechanism that directs the neuron specificity and subcellular placement of electrical synapses

2021 ◽  
Author(s):  
Sierra Palumbos ◽  
Rachel Skelton ◽  
Rebecca McWhirter ◽  
Amanda Mitchell ◽  
Isaiah Swann ◽  
...  
Keyword(s):  
Nervous System ◽  
Gap Junction ◽  
Motor Neurons ◽  
Live Cell Imaging ◽  
Cell Imaging ◽  
Electrical Synapse ◽  
Transcriptional Program ◽  
Electrical Synapses ◽  
C Elegans

Electrical synapses are established between specific neurons and within distinct subcellular compartments, but the mechanisms that direct gap junction assembly in the nervous system are largely unknown. Here we show that a transcriptional program tunes cAMP signaling to direct the neuron-specific assembly and placement of electrical synapses in the C. elegans motor circuit. For these studies, we use live cell imaging to visualize electrical synapses in vivo and a novel optogenetic assay to confirm that they are functional. In VA motor neurons, the UNC-4 transcription factor blocks expression of cAMP antagonists that promote gap junction miswiring. In unc-4 mutants, VA electrical synapses are established with an alternative synaptic partner and are repositioned from the VA axon to soma. We show that cAMP counters these effects by driving gap junction trafficking into the VA axon for electrical synapse assembly. Thus, our experiments in an intact nervous system establish that cAMP regulates gap junction trafficking for the biogenesis of electrical synapses.

scholarly journals Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function

2012 ◽  
Vol 23 (17) ◽  
pp. 3299-3311 ◽  
Author(s):  
Oscar Jara ◽  
Rodrigo Acuña ◽  
Isaac E. García ◽  
Jaime Maripillán ◽  
Vania Figueroa ◽  
...  
Keyword(s):  
Gap Junction ◽  
Transmembrane Domain ◽  
Critical Role ◽  
Full Length ◽  
Intermediate Step ◽  
Wild Type ◽  
Gap Junction Channels ◽  
Junction Protein ◽  
And Function ◽  
Pore Domain

To identify motifs involved in oligomerization of the gap junction protein Cx26, we studied individual transmembrane (TM) domains and the full-length protein. Using the TOXCAT assay for interactions of isolated TM α-helices, we found that TM1, a Cx26 pore domain, had a strong propensity to homodimerize. We identified amino acids Val-37–Ala-40 (VVAA) as the TM1 motif required for homodimerization. Two deafness-associated Cx26 mutations localized in this region, Cx26V37I and Cx26A40G, differentially affected dimerization. TM1-V37I dimerized only weakly, whereas TM1-A40G did not dimerize. When the full-length mutants were expressed in HeLa cells, both Cx26V37I and Cx26A40G formed oligomers less efficiently than wild-type Cx26. A Cx26 cysteine substitution mutant, Cx26V37C formed dithiothreitol-sensitive dimers. Substitution mutants of Val-37 formed intercellular channels with reduced function, while mutants of Ala-40 did not form functional gap junction channels. Unlike wild-type Cx26, neither Cx26V37I nor Cx26A40G formed functional hemichannels in low extracellular calcium. Thus the VVAA motif of Cx26 is critical for TM1 dimerization, hexamer formation, and channel function. The differential effects of VVAA mutants on hemichannels and gap junction channels imply that inter-TM interactions can differ in unapposed and docked hemichannels. Moreover, Cx26 oligomerization appears dependent on transient TM1 dimerization as an intermediate step.

scholarly journals A genetic basis for molecular asymmetry at vertebrate electrical synapses

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Adam C Miller ◽  
Alex C Whitebirch ◽  
Arish N Shah ◽  
Kurt C Marsden ◽  
Michael Granato ◽  
...  
Keyword(s):  
Gap Junction ◽  
Genetic Basis ◽  
Behavioral Performance ◽  
Electrical Synapses ◽  
Network Function ◽  
Molecular Asymmetry ◽  
Metabolic Coupling ◽  
Neuronal Synapses ◽  
Chemical Synapses ◽  
And Function

Neural network function is based upon the patterns and types of connections made between neurons. Neuronal synapses are adhesions specialized for communication and they come in two types, chemical and electrical. Communication at chemical synapses occurs via neurotransmitter release whereas electrical synapses utilize gap junctions for direct ionic and metabolic coupling. Electrical synapses are often viewed as symmetrical structures, with the same components making both sides of the gap junction. By contrast, we show that a broad set of electrical synapses in zebrafish, Danio rerio, require two gap-junction-forming Connexins for formation and function. We find that one Connexin functions presynaptically while the other functions postsynaptically in forming the channels. We also show that these synapses are required for the speed and coordination of escape responses. Our data identify a genetic basis for molecular asymmetry at vertebrate electrical synapses and show they are required for appropriate behavioral performance.

scholarly journals A genetic basis for molecular asymmetry at vertebrate electrical synapses

2017 ◽  
Author(s):  
Adam C Miller ◽  
Alex C Whitebirch ◽  
Arish N Shah ◽  
Kurt C Marsden ◽  
Michael Granato ◽  
...  
Keyword(s):  
Gap Junction ◽  
Genetic Basis ◽  
Behavioral Performance ◽  
Electrical Synapses ◽  
Network Function ◽  
Molecular Asymmetry ◽  
Metabolic Coupling ◽  
Neuronal Synapses ◽  
Chemical Synapses ◽  
And Function

AbstractNeural network function is based upon the patterns and types of connections made between neurons. Neuronal synapses are adhesions specialized for communication and they come in two types, chemical and electrical. Communication at chemical synapses occurs via neurotransmitter release whereas electrical synapses utilize gap junctions for direct ionic and metabolic coupling. Electrical synapses are often viewed as symmetrical structures, with the same components making both sides of the gap junction. By contrast, we show that a broad set of electrical synapses in zebrafish, Danio rerio, require two gap-junction-forming Connexins for formation and function. We find that one Connexin functions presynaptically while the other functions postsynaptically in forming the channels. We also show that these synapses are required for the speed and coordination of escape responses. Our data identify a genetic basis for molecular asymmetry at vertebrate electrical synapses and show they are required for appropriate behavioral performance.

scholarly journals Differential effect of subcellular localization of communication impairing gap junction protein connexin43 on tumor cell growth in vivo

Oncogene ◽  
2000 ◽  
Vol 19 (4) ◽  
pp. 505-513 ◽  
Author(s):  
V A Krutovskikh ◽  
S M Troyanovsky ◽  
C Piccoli ◽  
H Tsuda ◽  
M Asamoto ◽  
...  
Keyword(s):  
Cell Growth ◽  
Subcellular Localization ◽  
Tumor Cell ◽  
Gap Junction ◽  
Differential Effect ◽  
Tumor Cell Growth ◽  
Junction Protein ◽  
Gap Junction Protein

scholarly journals Two Drosophila Innexins Are Expressed in Overlapping Domains and Cooperate to Form Gap-Junction Channels

2000 ◽  
Vol 11 (7) ◽  
pp. 2459-2470 ◽  
Author(s):  
Lucy A. Stebbings ◽  
Martin G. Todman ◽  
Pauline Phelan ◽  
Jonathan P. Bacon ◽  
Jane A. Davies
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Ectopic Expression ◽  
In Vivo Studies ◽  
Electrophysiological Properties ◽  
Gap Junction Channels ◽  
Overlapping Domains ◽  
In Vitro Data

Members of the innexin protein family are structural components of invertebrate gap junctions and are analogous to vertebrate connexins. Here we investigate two Drosophila innexin genes,Dm-inx2 and Dm-inx3 and show that they are expressed in overlapping domains throughout embryogenesis, most notably in epidermal cells bordering each segment. We also explore the gap-junction–forming capabilities of the encoded proteins. In pairedXenopus oocytes, the injection of Dm-inx2mRNA results in the formation of voltage-sensitive channels in only ∼ 40% of cell pairs. In contrast, Dm-Inx3 never forms channels. Crucially, when both mRNAs are coexpressed, functional channels are formed reliably, and the electrophysiological properties of these channels distinguish them from those formed by Dm-Inx2 alone. We relate these in vitro data to in vivo studies. Ectopic expression ofDm-inx2 in vivo has limited effects on the viability ofDrosophila, and animals ectopically expressingDm-inx3 are unaffected. However, ectopic expression of both transcripts together severely reduces viability, presumably because of the formation of inappropriate gap junctions. We conclude that Dm-Inx2 and Dm-Inx3, which are expressed in overlapping domains during embryogenesis, can form oligomeric gap-junction channels.

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