---
# System prepended metadata

title: GAP junctions
tags: [page, Cell interaction]

---

---
title: GAP junctions
disqus: hackmd
---
GAP junctions
===
:::success
> Documentation [name=MrDr.Staffan]
###### tags: `page`, `Cell interaction`
:::


:::info
### Table of Contents
[TOC]
:::
[Top](#Table-of-Contents)

---

[Also See Filaments](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2F7uFEvjjARKCtBkF2MFRR6w)
Acyl- 






[2.4. Octanol and heptanol](https://www.sciencedirect.com/science/article/pii/S0278584608003989?via%3Dihub#bib139:~:text=2.4.%20Octanol%20and%20heptanol)

Long-chain alcohols, octanol (0.5–1 mM) and heptanol (1–3 mM), have been reported to block gap junctions in crayfish giant axons, rat glial cells and insect cells (Guan et al., 1997, Johnston et al., 1980, Weingart and Bukauskas, 1998). There is no evidence for a strong selectivity of these alcohols for any particular subtype of gap junction channels in mammalian cells (Spray et al., 2002). Octanol (1 mM) has been also found to block the Cx46 and Cx50 gap junction hemichannels (unpaired connexons) with a similar potency as gap junction channels (Eskandari et al., 2002).





# Cadherin

**Ca**lcium **de**pendent **ad**hesion
Transmembrane structural protein


# Protocadherins
three related gene clusters tandemly linked on chromosome five. The gene clusters demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters

The extracellular domains interact in a homophilic manner to specify differential cell-cell connections

---

## alpha complex - PCDHA@
* The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences

* The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster 
    - [#Comparable to Heavy-chain immunoglobins?]

* The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain

---

## beta complex - PCDHB@
* beta cluster contains 16 genes and 3 pseudogenes, each encoding 6 extracellular cadherin domains and a cytoplasmic tail that deviates from others in the cadherin superfamily

* Unlike the alpha and gamma clusters, the transcripts from these genes are made up of only one large exon, not sharing common 3' exons as expected

### PCDHB14 Neuronal
Diseases associated with PCDHB14 include Neurotic Disorder

---

## gamma complex - PCDHG@
* The gamma cluster includes 22 genes divided into 3 subfamilies, all part of the cadherin superfamily

* Subfamily A contains 12 genes
Subfamily B contains 7 genes and 2 pseudogenes
Subfamily C contains 3 genes (more distantly related)

* In addition, ORNT2 and TAF2F are included in the cluster due to their localization between protocadherin clusters beta and gamma on chromosome five

    - ORNT2=SLC25A2 mitochondrial **ornithinin transporter**.

    - TAF2F=TAF7 is an intronless **transcription co-activator**. component of the TFIID/TBP/TATA-binding protein complex (Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides)

22 large, variable region exons followed by a constant region, which contains 3 exons shared by all protocadherin genes in the cluster.[#Comparable to lambda-chain immunoglobins]

### PCDHGC3 Astrocytic


---

# Electrical synapses




Heme bound to potassium channels

a mitochondrial hemeprotein is likely to serve as an O2 sensor for K+ channels,

[See Co2](https://hackmd.io/@sholmqvist/BJpKurTBB/https%3A%2F%2Fhackmd.io%2F5WeiKeHbTsCQkizzoVeGnw#carbon-monoxide-CO)

# GAP junctions

Connexins: Key Players in the Control of Vascular Plasticity and Function
https://sci-hub.se/10.1152/physrev.00010.2019

Poskanzer, K. E., & Molofsky, A. V. (2018). Dynamism of an Astrocyte In Vivo: Perspectives on Identity and Function. Annual Review of Physiology, 80(1), 143–157. 
https://sci-hub.se/10.1146/annurev-physiol-021317-121125


Gap channels (gap junctions) are specialized cell-cell contacts that provide direct intracellular communication. They allow passive diffusion of molecules up to 1 kDa, including nutrients, metabolites (glucose), ions (K+, Ca2+) and second messengers (IP3, cAMP).


The complexity of astrocytes is further enhanced by the expression of connexins which form gap junctions (Giaume et al., 2005; Orthmann-Murphy et al., 2008). This feature allows the formation of a syncytium whereby astroglia communicates intercellularly. Gap junction coupling is not static and is modulated by a number of signaling pathways (Anders et al., 2014). Mainly, sensory, cognitive and emotional patterns transmitted from spatially distributed neuronal and glial populations can result in the activation of astroglial calcium waves that can be transmitted across the astrocytic syncytium (Pereira and Furlan, 2010).]




Gja1  Cx43
Gja5 Cx40
tjp2


## GJB6 Cx30 
Connexin-30 (GJB6) is a gap junction subunit expressed abundantly in brain and cochlea (summary by Dahl et al., 1996; Lautermann et al., 1998)

Cx30 is reduced in cortex during hibernation.
Associated with human deafness  (sensorineural deafness)
KO gives deafness due to lack of electric potential differnce.

Teubner et al. (2003) generated Gjb6-deficient mice by deletion of the Gjb6 coding region. Homozygous null mutants were born at the expected Mendelian frequency, developed normally, and were fertile; however, they exhibited a severe constitutive hearing impairment. From the age of hearing onset, these mice lacked the electrical potential difference between the endolymphatic and perilymphatic compartments of the cochlea (i.e., the endocochlear potential), which plays a key role in the high sensitivity of the mammalian auditory organ

Impaired trafficking was rescued by oligomerization with both CX26 and CX30, suggesting that CX26 and CX30 can form heteromeric connexons [OMIM]

. Knockout of the astroglial connexins Cx30 and Cx43 alters astroglial end foot morphology and reduces the barrier function of the brain vessels,
especially under conditions of elevated perfusion pressure
(135).

One of the connexin proteins [connexin 30 (Cx30)] that forms gap junctions between astrocytes can influence synaptic strength via the degree of astrocytic invasion into the synaptic space (68)https://sci-hub.se/10.1146/annurev-physiol-021317-121125

## Blockers
	
Flufenamic acid - approved
Channel blocker, Inhibitor, Pore Blocker, Antagonist	Calcium-activated chloride channel blocker; NSAID. Also activates TRPC6	

Carbenoxolone - Experimental
Inhibitor		

octanol - Investigational
Inhibitor	


## GJB2 Cx26
 sensorineural deafness
related pathways Development Slit-Robo signaling. 
## GJC2


![](https://i.imgur.com/bS4p3ho.png)


![](https://i.imgur.com/pT2iDRd.png)

![](https://i.imgur.com/cQQjAcX.png)


## Molecular weights <1kDa

![](https://i.imgur.com/rHzCPxb.png)
Nucleotides


![](https://i.imgur.com/jfj3b1F.png)
Amino Acids



![](https://i.imgur.com/rldSZ7c.png)
Salts


[Peptide calculator](https://www.biopeptide.com/PepCalc/HowItWorks)

http://www.rcsb.org/pdb/results/results.do?tabtoshow=Current&qrid=A7A91F38
Search all proteins smaller than 1200 Da

Search metabolites <1200 Da
https://hmdb.ca/unearth/advanced/metabolites#results







## >1kDa

![](https://i.imgur.com/3AQu6Vg.png)


# Cell-to-Cell

## LPHNs/ADGRL (Latrophilins)

Adhesion G Protein-Coupled Receptor L1 (ADGRL1)

Adhesion-like G-protein-coupled receptors implicated in attention-deficit/hyperactivity disorder.

![](https://i.imgur.com/fntbntd.png)


LPHN1/Adgrl1
Expresed neurons + others

LPHN2/Adgrl2
Expressed mainly in neurons. 
Downregulated with MS (Schrimer 2019)



LPHN3/Adgrl3
Neural cell types. Less in oligos.

## FLRTs (Fibronectin Leucine Rich Transmembrane Protein)

Flrt1
Low Oligos, OPCs, neurons(IN-VIP, EN-PYR)


Flrt2
Strong in Neurons, astrocytes some in microglia. None in oligodendrocytes.


Flrt3 
Low in neurons. Not in Oligos or astrocytes.

functions in cell-cell adhesion, cell migration and axon guidance, exerting an attractive or repulsive role depending on its interaction partners. Plays a role in the spatial organization of brain neurons. Plays a role in vascular development in the retina (By similarity).




# List of Cadherins (Oldham, mind human genes, but lower case)
() = Astro enriched?

![](https://i.imgur.com/lCgtn4D.png)

![](https://i.imgur.com/NqthYCe.png)

pcdh1
pcdh10 
pcdh11x
pcdh12
pcdh15
pcdh17 early oligo
pcdh18
pcdh19
pcdh20
pcdh7

pcdh8
pcdh9
pcdha1
pcdha10 (Mm pcdha9, oligo)
pcdha11
pcdha12 
pcdha13 (Mm pcdha12)
pcdha2
pcdha3
pcdha4
pcdha5

---

![](https://i.imgur.com/u4aLEEI.png)

![](https://i.imgur.com/zp5880B.png)

pcdha6
pcdha7
pcdha8

pcdhac1
pcdhac2
pcdhb1 - Ependymal only
pcdhb10 - glia
pcdhb11
pcdhb12
pcdhb13

pcdhb14
pcdhb15
pcdhb16
pcdhb2
pcdhb3
pcdhb4 ()
pcdhb5
pcdhb6
pcdhb7
pcdhb8

---

![](https://i.imgur.com/SJXgUqT.png)

![](https://i.imgur.com/zRcwnaA.png)

pcdhb9
pcdhga1 (glia)
pcdhga10 (glia)
pcdhga11 ()
pcdhga12
pcdhga2 ()
pcdhga3
pcdhga4
pcdhga5 ()
pcdhga6
pcdhga7

pcdhga8
pcdhga9
pcdhgb1
pcdhgb2
pcdhgb3 (not in mouse)
pcdhgb4
pcdhgb5
pcdhgb6
pcdhgb7 ()
pcdhgc3 ()
pcdhgc4 (not found)
pcdhgc5

---


# Endothelial cell junctions
![](https://hackmd.io/_uploads/BJf8XFn-h.png)


![](https://hackmd.io/_uploads/rJLG7FhZn.png =400x)

Lyve1
Jam-A
Claudine 5
Ctnnb1
Cdh5
Pcam1
Syndecan4
https://www.frontiersin.org/articles/10.3389/fphys.2020.00509/full

# Aquaporins
Mip // AQP0
Related - VRACs volume regulated anion channels



[compare the high res mri (Duke uni) with Expression of aqp and all other h20 carrying channels.?]

[Do all channels transport water in addition To tHeir assigneD (and unknown)  Substrate(-s) ?] 


[![image](https://hackmd.io/_uploads/SkYdJ3NL6.png =200x)2020 AQP4ex](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073200/)


# Connexin pairing and pannexin

![image](https://hackmd.io/_uploads/SkgmO4b46.png)

https://bmcmolcellbiol.biomedcentral.com/articles/10.1186/s12860-016-0089-5