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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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