C O N N E X I N P P T T T T T T T
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- 1.Connexin Proteins & Skin Diseases ) (By Prof .Dr . Mahmoud Yousry M .Abdel - Mawla* Professor of Dermatology & Venereology. Zagazig Faculty of Medicine,EGYPT .
2. CELL-TO-CELL COMMUNICATION
- Cell-to-cell communication can bemediated through different types of cell-to-cell junctions1- Gap junction2- Tight junction
- 3- Adherens junction4- Desmosome
- 5- Hemidesmosome
3. Fig. (1) : Cell-to-cell junctions 4. Gap Junctional Intercellular Communication(GJIC)
- It is the type ofcell-to-cell communication which enables cells to exchange signals directly through tiny tunnels known as :
- (( Gap Junctions ))
5. Gap Junction, Connexon and 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 ))
6. Fig. (2) : Connexin, connexon and gap junction 7. 8. Connexin 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.
9. Table (1: (Connexin nomenclature and sites of expression . N= name, Cx = connexin and kDa = kilodaltons 10. 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
11. Fig. (5):Connexin life cycle 12. Role Of Gap Junction In Different Systems
- It seems that gap junction plays an important role in almost all body organs including :
Skin Tissue inflammationand repair system Immune system Reproductive system Auditory system Cardiovascular system Ocularsystem Digestive system Nervous system 13. 14. Skin and Connexin
- Connexin expression and human skin development
- Connexin and wound healing
- Connexin in skin disorders (Connexinopathies) :
- Connexin and skin tumours
- Gap junction as a therapeutic target :
15. Connexin Expression and Human Skin Development
- The major connexins of the human epidermis are Cx26 and Cx43. In human fetal skinmore 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 . 16. Connexin 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.
17. Connexins in Skin Disorders (Connexinopathies) 18. Evidences upon role of connexin in keratinocytes proliferation & differentiation
- 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.
- 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.
- Cx37 and Cx31.1, are also induced in psoriasis and erythrokeratoderma variabilis.
- In hyperproliferative skin conditions (likepsoriasis ) there is an impressive up-regulation of Cx26 in psoriatic plaques.
20. Erythrokeratoderma variabilis (EKV)
- Clinical features :
- -Usually presents in the first year oflife
- - With two characteristic lesions :
- erythematousareas 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.
21. Fig .(7) :EKV Migratoryerythematous lesions Fig. (9) (a) A patient with EKV (b) The same patient after 3 weeks. Note that shapes of thelesions have greatly changed overtime.Fig. (8) :EKV Hyperkeratoticfixed plaques on legs and buttocks 22. Aetiology and pathogenesis
- EKV has been found to be a disorder ofconnexinwith a dominant mode of inheritance, but rarely recessively inherited.
- Mutations have been identified mainly in
- (( Cx 31 gene )) .
- These mutations affect the transmembrane domains and hinder the kinetics of channel closure.
- Some mutations involve the cytoplasmic amino-terminus of Cx 31 or Cx 30.3.
24. Palmoplantar keratoderma and sensorineural hearing loss
- Keratitis-ichthyosis-deafness (KID) syndrome
- Clinical features :
- KID syndrome is themost severecutaneous 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.
- 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.
26. Fig. (10) : KID syndrome 27. Aetiology and pathogenesis
- Keratitis-ichthyosis-deafness syndrome can be caused by mutations in 2 closely related connexin genes, GJB2((Cx26))and GJB6((Cx30)) .
28. Hidrotic ectodermal dysplasia (HED) syndrome
- Clinical features :
- -Hypotrichosis and progressive nail dystrophy.
- -Function of sweat andsebaceous glands is normal.
29. Aetiology and pathogenesis
- The underlying basis ofHEDsyndrome 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.
- 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.
- However, continual stimulation depletes calcium stores and desensitizes ATP receptors from responding to differentiation signals.
- Furthermore, keratinocyte release of ATP exacerbates inflammation by activatingLangerhans cells .
- Therapies aiming at decreasing Cx26 levels may provide a therapeutic benefit by reestablishing the epidermal barrier and modulating the skin inflammatory response in psoriasis.
32. Connexin 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.
- Moreover,in BCCthere 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.
- 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.
- (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.
- This leads to abnormal gap junction communication between malignant cells and host cells could underlie the dysregulated proliferation and invasion of tumor cells.
37. Gap junction as atherapeutic target 38. Gap junction as a target in cancer chemoprevention and chemotherapy
- The inhibitory effects of tumour promoters on GJIC can be blocked by many agents like dietary factors, hormones, vitamins, and pharmaceuticals.
- The enhancement of GJIC in fully malignant cells by chemopreventive agents might be a difficult task although there are many demonstrations of success.
- So ,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 o