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Connexin ProteinsConnexin Proteins& Skin Diseases& Skin Diseases

) ( ByBy

ProfProf. . DrDr..

Mahmoud Yousry MMahmoud Yousry M. . AbdelAbdel--Mawla*Mawla*Professor of Dermatology & Venereology.Professor of Dermatology & Venereology.

Zagazig Faculty of Medicine,EGYPTZagazig Faculty of Medicine,EGYPT

..

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CELL-TO-CELL CELL-TO-CELL COMMUNICATIONCOMMUNICATION

Cell-to-cell communication can be mediated mediated

through different types of cell-to-cell junctions through different types of cell-to-cell junctions

1- Gap junction 2- Tight junction 1- Gap junction 2- Tight junction

3- Adherens junction 4- Desmosome 3- Adherens junction 4- Desmosome

5- Hemidesmosome5- Hemidesmosome

33Fig. (1) : Cell-to-cell

junctions

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Gap Junctional Intercellular Gap Junctional Intercellular Communication(GJIC)Communication(GJIC)

It is the type of cell-to-cell communication It is the type of cell-to-cell communication

which enables cells to exchange signals directly which enables cells to exchange signals directly

through tiny tunnels known as :through tiny tunnels known as :

(( Gap Junctions ))(( Gap Junctions ))

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Gap Junction, ConnexonGap Junction, Connexonand Connexinand Connexin

Gap junctions are formed of two hemi-channel

transmembrane protein structures named

(( connexons ))

Each connexon is made up of six

transmembrane protein subunits named

(( connexins ))

66Fig. (2) : Connexin, connexon and gap

junction

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Connexin NomenclatureConnexin Nomenclature

The most widely used system uses the word

connexin (often abbreviated Cx) followed by a suffix

indicating the molecular mass of the polypeptide in

kilodaltons.

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Table (1 : ( Connexin nomenclature and sites of expression.

N= name, Cx = connexin and kDa = kilodaltons

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Connexin Biosynthesis &Degradation

The life cycle of a Cx polypeptide can be summeraized in the following steps :

1-Connexin polypeptide biosynthesis

2-Oligomerization

3-Trafficking to the cell surface

4-Insertion and docking of connexon

5-Aggregation of gap junction into plaques

6-Internalization

7-Gap junction removal and degradation

1111Fig. (5) : Connexin life cycle

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Role Of Gap JunctionRole Of Gap JunctionIn Different SystemsIn Different Systems

It seems that gap junction plays an

important role in almost all body organs including

: Skin

Tissue inflammation and repair system Immune system

Reproductive system Auditory system

Cardiovascular system Ocular system

Digestive system Nervous system

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Skin and ConnexinSkin and Connexin

Connexin expression and human Connexin expression and human skin development skin development

Connexin and wound healing Connexin and wound healing Connexin in skin disorders Connexin in skin disorders

(Connexinopathies) :(Connexinopathies) : Connexin and skin tumours Connexin and skin tumours Gap junction as a therapeutic Gap junction as a therapeutic

target : target :

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Connexin Expression and Connexin Expression and Human Skin DevelopmentHuman Skin Development

The major connexins of the human epidermis are Cx26 and Cx43. In human fetal skin more gap junctions are observed as the gestational age increases and more gap junctions are observed in the upper layer.

Fig . (6) : Gap junction distribution during human skin development.

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Connexin and Wound HealingConnexin and Wound Healing

The different stages of wounding are

accompanied by striking changes in connexin

expression in both the epidermis and dermis, and

individual connexins can be correlated with key

events in the wound healing process.

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Connexins in Skin DisordersConnexins in Skin Disorders

(Connexinopathies)(Connexinopathies)

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Evidences upon role of connexin in Evidences upon role of connexin in keratinocytes proliferation & differentiationkeratinocytes proliferation & differentiation

1. Wounding of adult rat tail is associated with a

strong up-regulation of Cx26 expression in

differentiated cells proximal to the wound edge,

while the expression of Cx31 and Cx43 declines.

2. In human skin, tape stripping resulted in an

induction of Cx26 expression in a patchy pattern

in the basal cell layer that preceded an increase

in cell proliferation.

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3. Cx37 and Cx31.1, are also induced in psoriasis

and erythrokeratoderma variabilis.

4. In hyperproliferative skin conditions (like

psoriasis) there is an impressive up-regulation of

Cx26 in psoriatic plaques.

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Erythrokeratoderma variabilis Erythrokeratoderma variabilis (EKV)(EKV)

Clinical features :-Usually presents in the first year of life - With two characteristic lesions :

erythematous areas which vary in shape and position over time.hyperkeratotic, well-defined, more stable plaques.

The lesions have a predilection for the extensor aspects of the limbs, the lateral trunk and the buttocks.

-Hair, teeth and nails are normal.

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Fig .(7) : EKV Migratory

erythematous lesions

Fig. (9) (a) A patient with EKV

(b) The same patient after 3 weeks.

Note that shapes of the lesions have

greatly changed over time.

Fig. (8) : EKVHyperkeratotic

fixed plaques on legs and buttocks

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Aetiology and pathogenesis

EKV has been found to be a disorder of EKV has been found to be a disorder of

connexinconnexin with a dominant mode of inheritance, but with a dominant mode of inheritance, but

rarely recessively inherited.rarely recessively inherited.

Mutations have been identified mainly in Mutations have been identified mainly in

(( Cx 31 gene ))(( Cx 31 gene ))..

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These mutations affect the transmembrane These mutations affect the transmembrane

domains and hinder the kinetics of channel domains and hinder the kinetics of channel

closure.closure.

Some mutations involve the cytoplasmic Some mutations involve the cytoplasmic

amino-terminus of Cx 31 or Cx 30.3.amino-terminus of Cx 31 or Cx 30.3.

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Palmoplantar keratoderma and Palmoplantar keratoderma and sensorineural hearing loss sensorineural hearing loss

Keratitis-ichthyosis-deafness (KID) syndromeKeratitis-ichthyosis-deafness (KID) syndrome

Clinical features :

KID syndrome is the most severe cutaneous

connexin disorder.

Cutaneous features :

-Well circumscribed hyperkeratotic plaques with

underlying erythema on the extremities and face

usually manifest at birth.

-PPK with a grainy-appearing surface.

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Ophthalmologic features : :

Corneal neovascularization which may cause

progressive visual decline and blindness.

Auditory features :

Congenital, bilateral, and severe to profound

SNHL.

The syndrome is associated with increased

susceptibility to mucocutaneous infections and

squamous cell carcinoma of the skin and oral

cavity.

2626FigFig . .(10) : KID syndrome(10) : KID syndrome

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Aetiology and pathogenesis

Keratitis-ichthyosis-deafness syndrome can be

caused by mutations in 2 closely related connexin

genes, GJB2 ((Cx26)) and GJB6 ((Cx30)).

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Hidrotic ectodermal dysplasia Hidrotic ectodermal dysplasia (HED) syndrome(HED) syndrome

Clinical features :Clinical features :

-Hypotrichosis and progressive nail dystrophy.

-Function of sweat and sebaceous glands is normal.

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Aetiology and pathogenesis

The underlying basis of HED syndrome is

missense mutations in the ((Cx30 gene)), GJB6.

These mutations impair trafficking of the mutant

protein to the cell membrane thus resulting in a

complete loss of gap junction function.

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PsoriasisPsoriasis

Connexin 26 is one of the most highly upregulated genes in psoriatic plaques.

ATP release from Cx26 hemichannels activates purinergic receptors on keratinocytes and Langerhans cells.

In keratinocytes, this results in a rise of intracellular calcium.

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However, continual stimulation depletes calcium stores and desensitizes ATP receptors from responding to differentiation signals.

Furthermore, keratinocyte release of ATP Furthermore, keratinocyte release of ATP exacerbates inflammation by activating exacerbates inflammation by activating Langerhans cellsLangerhans cells..

Therapies aiming at decreasing Cx26 levels may Therapies aiming at decreasing Cx26 levels may provide a therapeutic benefit by reestablishing the provide a therapeutic benefit by reestablishing the epidermal barrier and modulating the skin epidermal barrier and modulating the skin inflammatory response in psoriasis.inflammatory response in psoriasis.

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Connexin and skin tumoursConnexin and skin tumours

(A) Keratinocyte-derived skin tumours

There is an induction of Cx26 and Cx30 in basal cell

carcinoma and in squamous cell carcinoma while

there is either no change or a downregulation of

Cx43.

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Moreover, in BCC there is an induction of Cx26

and Cx30 in tumor areas deep in the dermis

compared to those close to the epidermis,

suggesting an increase in Cx expression in

invasive areas of the BCC.

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In SCC, there was a correlation between staining

reactivity and tumor differentiation. Highly

differentiated cells are clearly positive, while less

differentiated cells are weakly positive for Cx26

and Cx30.

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(B) Non-keratinocyte-derived skin tumours

In malignant melanoma :

-There is a lack of Cx43.

-No induction of Cx26 and Cx30.

-Altered expression profile of cadherin molecules and

a subsequent switch to atypical gap junction partners.

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This leads to abnormal gap junction

communication between malignant cells and host

cells could underlie the dysregulated proliferation

and invasion of tumor cells.

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Gap junction as a therapeutic Gap junction as a therapeutic targettarget

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Gap junction as a target in cancer Gap junction as a target in cancer chemoprevention and chemotherapychemoprevention and chemotherapy

The inhibitory effects of tumour promoters on

GJIC can be blocked by many agents like dietary

factors, hormones, vitamins, and pharmaceuticals.

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The enhancement of GJIC in fully malignant cells

by chemopreventive agents might be a difficult

task although there are many demonstrations of

success.

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SoSo, , the enhancement of GJIC in neoplastic cells will have several beneficial therapeutic effects.

These include :

1-Decreased cell proliferation

2-Increased differentiation

3-Increased ability to apoptosis

4-Increased bystander effect

5-Increased efficacy of chemotherapy and radiation therapy

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Gap junction as a target for two Gap junction as a target for two human teratogeneshuman teratogenes

Both retinoic acid and thalidomide are human

teratogens that can stimulate GJIC.

Since GJIC has an important effect on

embryogenesis, there could be a link between

teratogenicity of these agents and their effects on

GJIC.

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Gap junction as a target in wound Gap junction as a target in wound healinghealing

Based on changes in connexin distribution during

skin wound healing, targeting of specific connexins

could provide a new approach for improving

therapy of acute and chronic skin wounds.

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Gap junction as a target in gene Gap junction as a target in gene therapytherapy

A connexin gene therapy seems to be a logical

therapeutic approach. However gene therapy has

many distinct problems including vector toxicity

and inefficient target cell transduction.

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SUMMARY AND CONCLUSIONSUMMARY AND CONCLUSION

Cell-to-cell communication via gap junctions

is crucial for normal cellular growth and

differentiation.

Connexin proteins are members of a family

of at least 20 proteins that form gap junction

channels.

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Gap junction plays an important role in

almost all body organs including the skin.

Many skin disorders are due to a defective

gap junction such as EKV, PPK & SNHL and skin

tumours.

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SoSo, , based upon the association between connexin proteins and skin diseases, it

is highly likely that a good understanding of connexin biology will provide novel therapeutic insights and

an exciting challenges for the future………………….

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