ashish cell adhesion

8/7/2019 ashish CELL ADHESION

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CONTENT

CELL-CELL INTERACTION

CELL ADHESION

CADHERINS

SELECTIN

INTEGRINS

IMMUNOGOBULIN FAMILY

CELL JUNCTION

OCCULUDING JUNCTION

TIGHT JUNCTIONSEPTATE JUNCTION

ANCHORING JUNCTION

ADHEREN JUNCTION

FOCAL JUNCTION

DESMOSOMES

HEMI-DESMOSOMES

COMMUNICATING JUNCTION

GAP JUNCTION

PLASMDESMATA

CHEMICAL SYNPASES

SUMMARY

BIBLOGRAPHY


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CELL ADHESION

Cell-cell adhesion is a selective process such that

cells adhere only to other cell of specific types.

This selectivity was first demonstrated in

classical studies of embryo development, whichshowed that cells from one tissue (e .g. liver)

specifically adhere to cell of the some tissue

rather than to cells of a different tissue (e.g.

brain).

Such selective cell-cell adhesion is mediated by

trans- membrane protein called cell adhesion

molecules (CAM)


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CELL ADHESION

TYPES OF CELL ADHESION

1. CELL-CELL ADHESION

2. CELL-EXTRACELLULAR MATRIX


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CELL ADHESION MOLECULES

Cell adhesion molecules are protein located on

the cell surface involved with the binding with

other cells or with the extracellular matrix

(ECM) in the process called cell adhesion.

Are typically trans-membrane receptor and are

composed of three domains : an intracellular

domains that interacts with cytoskeleton, a trans

membrane domain and an extracellular domain

that interacts with other CAMs of same kinds(hemophilic binding ) or with other CAMs or the

extracellular matrix (heterophilic binding)


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CELL ADHESION MOLECULES ARE DIVIDED

INTO FOUR MAJOR GROUPS

1. SELECTIN

2. INTEGRINS

3. CADHERINS

4.IMMUNOGLOBULIN SUPERFAMILY (Ig)


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CELL ADHESION INTERACTION HOMOPHILIC BINDING : Interaction in which an

adhesion molecule on the surface of one cell binds to thesame molecule on the surface of another cell.

HETROPHILIC BINDING : Interaction in which an

adhesion molecule on the surface of one cell recognizes a

different molecule on the surface of another cell (eg.

selectin and an integrin) LINKER DEPENDENT BINDING: Interaction of adjacent

cell adesion molecule on the surface of two cell binds with a

help of linker molecule.


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CADHERIN

Expressed in both invertebre and vertebrate

Are main molecules holding cells together in early

embryonic tissue

Homophilic binding

Calcium dependent

formation of adheren junction and desmosomes

Most cadherin are single pass trans-membrane

glycoproteins about 700-750 amino acid long.

They associate in the plasma membrane to formdimmers or larger oligomers as extracellular part of

the polypeptide chain which is usually folded into five

or six cadherin repeats, which are structurally related

to immunoglobulin (Ig) domains


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The Ca2+ ions are positioned between each pair

of cadherin repeats, locking the repeats together to

form a stiff, rod like structure: the more Ca2+ ions

that are bound, the more rigid the structure is.

If Ca2+ is removed, the extracellular part of

the protein becomes floppy and is rapidly degraded

by proteolytic enzymes


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THE LINKAGE OF CLASSICAL CADHERINS TO ACTIN FILAMENTS

THE CADHERINS ARE COUPLED INDIRECTLY TO ACTIN FILAMENTS BY

THE ANCHOR PROTEINS -CATENIN AND -CATENIN. ATHIRD

INTRACELLULAR PROTEIN, CALLED P120, ALSO BINDS TO

THE CADHERIN CYTOPLASMIC TAIL AND

REGULATES CADHERIN FUNCTION. -CATENIN HAS A SECOND, AND

VERY IMPORTANT, FUNCTION IN INTRACELLULAR SIGNALLING.


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Divided as classical and non-classical cadherin

Classical cadherin are E-cadherin, P-cadherin and N-

cadherin and are widely expressed during earlydifferentiation

E-cadherin is present in epithelial cells; N-cadherin

in nerve cells and P-cadherin in placenta and

epidermis. Non-classical cadherins include proteins with known

adhesive function such as desmosomal cadherins and

protocadherin found in brain


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SELECTIN

Single trans-membrane protein with highly

consereved lectin domain

Heterophilic binding

Calcium dependent cell-cell adhesion in the

bloodstream.

Three types of selectin: L-selectin in blood

cells(leukocytes), P-selectin in blood platelets and

E-selectin in endothelial cells

They are attached to actin filament with an

anchor protein they collaborate with integrins, which strengthen

the binding of the blood cells to the endothelium.


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(A) The structure of P-selectin. The selectin attaches to the actin

cytoskeleton through anchor proteins that are still poorly characterized.

(B) How selectins andintegrins mediatethecell-celladhesions

required


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Are active during inflammatory response

have an important role in binding white blood

cells to endothelial cells lining blood vessels,

thereby enabling the blood cells to migrate out of

the bloodstream into a tissue


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INTREGRIN Heterophilic binding

Present in verterbrates

At least 24 integrin heterodimer composed of 18 types

of subunits and 8 types of subunits in various

combination.

Integrin subunits span the plasma membrane and in

general have very short cytoplasmic domains of about

4070 amino acids where as beta-4 subunits have

1088 amino acid

The molecular mass of the integrin subunits can vary

from 90 kDa to 160 kDa Helps in focal adhesion and hemi-desmosomes


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Protein named Talin activates the newly formed integrin

which is bent in position, attaches to the tail

Calcium and magnesium dependent It is hepls in formation of focal adhesion by forming a

complex of ligand, integrin molecule and associste plaques

protein

Not only do integrins perform this outside-in signalling,

but they also operate an inside-out mode. Thus,they transduce information from the ECM to the cell as

well as reveal the status of the cell to the outside, allowing

rapid and flexible responses to changes in the

environment, for example to allow blood coagulation by

platelets.

Integrins bind to extra-cellular proteins via short amino

acid sequences, such as the R-G-D sequence motif (found

in proteins such as fibronectin, laminin, or vitronectin)


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IMMUNOGLOBULIN SUPERFAMILY

categorized as members of this superfamily based on

shared structural features with immunoglobulins(also known as antibodies)

Calcium independent

Homophilic binding

Proteins of the IgSF possess a structuraldomain known as an immunoglobulin (Ig) domain.

contain about 70-110 amino acids and are categorized

according to their size and function

Ig-domains possess a characteristic Ig-fold, whichhas a sandwich-like structure formed by two sheets of

anti-parallel beta strands.


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Among IgCAMs are neural CAMs, intercellular CAMs

(ICAMs) which function in the movement of leukocytes

into tissue and junction adhesion molecules (JAMs)

which are present in tight junction.

NCAMs play important role in he differentiation of

muscle, glial and nerve cell.

NCAMs comprises of extracellular region with five Ig

repeats and two fibronectin type III repeats, a singlemembrane-spanning segment and cytosolic segment

that interacts with the cytoskeleton.

In human, gene mutation in L1-CAM causes various

neuropathologies(e.g. mental retardation, congentialhydrocephalus and spasticity)


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CELL JUNCTION

Cell junction is a type of structure that existswithin the tissue of a multi-cellular organism.

They consist of protein complexes and provide

contact between neighboring cell or between a

cell and the extra cellular matrix or they buildupthe paracellular barrier of epithelia and control

the paracellular transport.

Cell junctions are especially abundant in

epithelial tissue.


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CELL JUNCTION CAN BE CLASSIFIED INTO

THREE FUNCTIONAL GROUP

OCCULUDING JUNCTION: Junction that seal celltogether in an epithelium in a way that prevents

even small molecule from leaking from one side

of the sheet to the other.

ANCHORING JUNCTION: Mechanically attachescell (and their cytoskeletons) to their neighbors or

to the extracellular matrix.

COMMUNICATING JUNCTION: Mediates the

passage of chemical or electrical signal from one

interacting cell to its proteins


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1.Occluding junctions

a.tight junctions

b.sepate junction2. Anchoring junctions

a. actin filamentattachmentsitesi. cell-cell adherens junctions (e.g., adhesion

belts)

ii. cell-matrix adherens junctions (e.g., focalcontacts)

b. intermediatefilamentattachmentsitesi. cell-cell adhesion (desmosomes)ii. cell-matrix adhesion (hemi-desmosomes)

3. Communicating junctionsa. gap junctionsb. chemical synapsesc. plasmodesmata (plants only)


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OCCLUDING JUNCTION

TIGHT JUNCTION:

present in vertebrates.

the epithelial cells lining the small intestine form a barrierthat keeps the gut contents in the gut cavity, the lumen.

the tight junctions between epithelial cells are thought tohave both of these roles.

first, they function as barrier to the diffusion of somemembrane proteins between apical and basolateraldomains of the plasma membrane. Mixing of such proteinand lipid occur if tight junction are disrupted by removingthe extra cellular Ca2+ that is required for tight junctionintegrity.

Second, tight junction seal neighboring cells together so

that if a low-molecular weight tracer is added to one side ofan epithelium, it will generally not pass beyond the tightjunction. Although all tight junction are impermeable tomacromolecule, their permeability to small molecule variesgreatly in different epithelia.


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SIMPLIFIED DRAWING OF A CROSS-SECTION THROUGH PART OF THE WALL

OF THE INTESTINE. THIS LONG, TUBELIKE ORGAN IS CONSTRUCTED

FROM EPITHELIAL TISSUES (RED), CONNECTIVE TISSUES (GREEN),

AND MUSCLE TISSUES (YELLOW). EACH TISSUE IS AN ORGANIZEDASSEMBLY OF CELLS HELD TOGETHER BY CELL-CELL ADHESIONS,

EXTRACELLULAR MATRIX, OR BOTH.


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Impermeable to macromolecule, their

permeability to small molecules varies greatly in

different epithelia. ability to restrict the passage of ions through the

spaces between cell is found logarithmically with

increasing number of strands in the network,thus

suggesting that strands acts as independentbarrier to ion flow

Major trans membrane protein are claudin and

occludin and also ZO which is essential for

formation of and function of tight junction.


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Role of tight junction in transcellular protein: Transport proteins are confined to different regions of the

plasma membrane in epithelial cells of the small intestine. This segregation permits a vectorial transfer of

nutrients across the epithelial sheet from the gut lumen to the blood. In the example shown, glucose is

actively transported into the cell by Na+-driven glucose symports at the apical surface, and it diffuses out of

the cell by facilitated diffusion mediated by glucose carriers in the basolateral membrane. Tight junctions are

thought to confine the transport proteins to their appropriate membrane domains by acting as diffusionbarriers within the lipid bilayer of the plasma membrane; these junctions also block the backflow of glucose

from the basal side of the epithelium into the gut lumen


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DISORDER RELATED TO TIGHT JUNCTION

Disruption of TJs leads to intestinal

hyperpermeability (the so-called "leaky gut")

which has been proposed by some researchers to

involve a relationship with acute and chronic

diseases such as systemic inflammatory response

syndrome (SIRS frequently a response of theimmune system to infection), inflammatory bowel

disease, type-1 diabetes, allergies, asthma,

and autism(impaired social interaction and

communication and restricted and repetative

behaviour)


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SEPTATE JUNCTION

Discovered by R.L. Wood 1959 found in invertebrate tissues adhesion, sealing,

communication septa walls regularly spaced

cross bars 15-17 nm .

This are main occluding junction in invertebrates

regular in structure than a tight junction , they

likewise form continuous band around each

epithielial cell. But their morphology is proteins

that are arranged in parallel rows with a regular

periodicity .


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Electron micrograph of a septate junction between two epithelial cells of a

mollusk. The interacting plasma membranes, seen in cross-section, are

connected by parallel rows of junctional proteins. The rows, which have aregular periodicity, are seen as dense bars or septa. (From N.B. Gilula, in

Cell Communication [R.P. Cox, ed.], pp. 1-29)


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A protein called Disc-large, which is required for

the formation of septate junction in Drosophila is

structurally related to the ZO protein found invertebrate tight junction.

Mutant flies that are deficient in this protein not

only lack septate function but also develop

epithelial tumors.

This observation suggests that the normal

regulation of cell proliferation in epithelial tissue

may depend in part on intra cellular signal that

emanate from occluding junction.


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ANCHORING JUNCTION

widely distributed in animal tissue and are most

abundant in tissue that are subjected to serve

mechanical stress such as heart, muscle and

epidermis.

composed of two main classes of protein-Intra

cellular anchor protein and Trans-membrane

adhesion proteins.


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Intracellular anchor protein:

proteins form a distinct plaque on thecytoplasmic face of the plasma membrane and

connect the junctional complex to either actin

filaments or intermediate filaments.

Trans-membrane adhesion protein :

protein have a cytoplasmic tail that binds to one

or more intracellular anchor protein and an

extracellular domains that interacts with either

the extracellular matrix or the extracellular

domains of specific trans-membrane adhesionprotein on another cell.


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Dependingupon Cytoskeletonattachment

sites anchoring junctionisclassifiedas

A). Actin filament attachment sites

1. adherens junction

2. focal adhesion

B). Intermedite filament attachment sites

1. Desmosomes

2. Hemi-desmosomes


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FOCAL ADHESION Integrin mediated junction

Enable cells to get hold on the extra-cellular matrixthrough integrins that link intra cellularly to actinfilaments .In this way muscle cells for example attachto their tendous at the myotendinous junction.

Likewise, when cultured fibroblast migrates on an

artificial substratum coated with extra-cellularmatrix molecules, they also grip the substratum atfocal adhesion where bundle of actin filamentterminate.

At all such adhesion , the extracellular domains oftrans-membrane integrin protein bind to a proteincomponent of the extra-cellular matrix , while theirintra-cellular domain bind indirectly to bundles ofactin filament via the intra-cellular anchor proteintalin, -actinin, filamin and vinculin.


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Function as signal carriers (sensors), which

inform the cell about the condition of the ECM

and thus affect their behavior

important role in the immune system, in which

white blood cells migrate along the connective

endothelium following cellular signals and to

damaged biological tissue Also active signalling during cell motility to cell

cycle


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DESMOSOMES Discovered by K.R. Porter in 1954

Homophilic interaction between trans-membraneprotein(Cadherin)

Through desmosomes the intermediate filament of

adjacent cell are linked into a net that extends

throughout the many cell of a tissue . The particular type of intermediate filament attached

to the desmosomes depend on cell type: they are

keratin filament in heart muscle cells .

The junction has a dense cytoplasmic plaque

composed of a complex of intra cellular anchor

proteins (plakoglobin and desmoplakin) that are

responsible for connecting the cytoskeleton to the

trans-membrane adhesion proteins.


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Found in muscle cells

Blistering diseases such as Pemphigus vulgaris

or Pemphigus foliaceus can be due to genetic

defects in desmosomal proteins.(epithelial cells of

skin)

patients who suffer from autoimmune diseases

characterized by skin and mucous membraneblistering produce autoantibodies against

desmogleins 1 and 3 (DSG1, DSG3). These two

observations suggested that the loss of normal

desmosome function could lead to tissue fragility

disorders.(cadherin based protein desmoglein and

desmocolin)


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HEMI-DESMOSOMES This are half-desmosomes resemble desmosomes

morphologically and in connecting tointermediate filament and like desmosomes they

act as rivets to distribute tensile or shearing

forces through an epithelium .Instead of joining

adjacent epithelial surface of an epithelial cell to

underlying basal lamina. The extracellular domains of the integrins that

mediate the adhesion bind to laminin protein in

the basal lamina while an intracellular domain

binds via an anchor protein (plectin) to keratinintermediate filaments.


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DISORDER DUE TO HEMI-DESMOSOMES

Epidermolysis Bullosa is a set of geneticallyinherited conditions affecting 1 in 17,000 of the

population. A fault in a gene causes the skin to be

extremely fragile. The layers of the skin do not

adhere properly and painful widespread blisters

occur very easily. These can lead to increasing

disfigurement, disability and in the most severe

forms death in early childhood.

Genes encoding different components of

hemidesmosomes have been found to be mutatedin various forms of hereditary bullous skin

disorders


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Table 19-2 Anchoring Junctions

Junction

Transmembrane Linker

Protein Extracellular Ligand

Intracellular

Cytoskeletal

Attachment

Some Intracellular

Attachment Proteins

Adherens

(cell-cell)

cadherin (E-cadherin) cadherininneighboring

cell

actin

filaments

catenins, vinculin, -

actinin, plakoglobin

Desmosome cadherin (desmogleins

& desmocollins)

cadherininneighboring

cell

intermediate

filaments

desmoplakins,

plakoglobin

Adherens

(cell-matrix)

integrin extracellularmatrix

proteins

actin

filaments

talin, vinculin, -actinin

Hemidesmos

ome

integrin extracellularmatrix (basal

lamina) proteins

intermediate

filaments

desmoplakinlike protein


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Gap junctions as seen in the electron microscope Thin section (A) and freeze


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Gap junctions as seen in the electron microscope. Thin-section (A) and freeze-

fracture (B) electron micrographs of a large and a small gap junction between fibroblasts

in culture. In (B) each gap junction is seen as a cluster of homogeneous intra-membrane

particles associated exclusively with the cytoplasmic fracture face (P face) of the plasma

membrane. (From N.B. Gilula, in Cell Communication [R.P. Cox, ed.], pp. 1-29)


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Permits the passage of molecules as large as 1.2 nm

in diameter (mammalian) and 2 nm in insects

Molecules smaller than 1200 Da can pass but lager

than that wont

Thus ion, low-molecular weight precursors of

cellular macromolecules, products of intermediary

metabolism and small intracellular signalingmolecules can pass

Gap junction composed of connexins, a family of

structurally related trans-membrane proteins which

consist of 21 different human protein. Innexins forms gap junction in invertebrates


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Determining the size of a gap-junction channel. When

fluorescentmoleculesof varioussizes areinjectedintooneoftwo

cellscoupledby gap junctions, moleculessmallerthan about 1000daltons can passintotheothercellbutlargermoleculescannot.


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Vertebrate hexagonal particle consists of 12

connexin molecules: 6 of the molecules are

arranged in connexon hemi-channel

Hexagonal cylinder of one plasma membrane

when joined to adjacent cell hemi-channel they

form a continuous aqueous channel between the

cell

Homotypic connexon : single type of connexin

Hetero-oligomeric connexon : two or more type of

connexin

plays a crucial role in the maintenance of

homeostasis, morphogenesis, cell differentiation,and growth control in multicellular organisms


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AMODEL OF A GAP JUNCTION. THE DRAWING SHOWS THE INTERACTING PLASMA

MEMBRANES OF TWO ADJACENT CELLS. THE APPOSED LIPID BILAYERS (RED) ARE

PENETRATED BY PROTEIN ASSEMBLIES CALLED CONNEXONS(GREEN),EACH OF

WHICH IS THOUGHT TO BE FORMED BY SIX IDENTICAL PROTEIN SUBUNITS

(CALLED CONNEXINS). TWO CONNEXONS JOIN ACROSS THE INTERCELLULAR GAP

TO FORM A CONTINUOUS AQUEOUS CHANNEL CONNECTING THE TWO CELLS.


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Gap junctions are not always open

Opening & closing is regulated by changes in pH

and Ca2+ concentration

High Ca2+, Low pH closed

Low Ca2+, high pH open


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DISORDERS IN GAP JUNCTION

Connexin 32 mutations cause X-linked Charcot-

Marie-Tooth disease, an inherited peripheraldemyelinating neuropathy.

Connexin 26 mutations have been found in hereditary

nonsyndromic sensorineural deafness. Connexin 43

knockout mice die shortly after delivery because of

cardiac malformation.

Neuronal gap junctions are involved in electrical

coupling and may also contribute to the recovery of

function after cell injury. Astrocytes are involved in

the pathology of most neuronal disorders, includingbrain ischemia, Alzheimer's disease and epilepsy.

In the pathology of brain tumors, gap junctions may

be related to the degree of malignancy and metastasis


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PLASMODESMATA

Plays a key role in plant development

Adhesion between plant cells is mediated by their cellwalls rather than by trans-membrane proteins. Inparticular, specializes pectin-rich region of the cellwall called the middle lamella acts as a glue to holdadjacent cells together.

Because of the rigidity of plant cell walls, stable

association between plant cells do not require theformation of cytoskeleton links such as those providedby the desmosomes and adherens junction of animalcells.

adjacent plant cell communicate with each otherthrough cytoplasmic connection called plasmodesmata

(singular, plasmodesma). Although distinct in structure, plasmodesmata

function analogously to gap junction as means ofdirect communication between adjacent cells intissues.

PLASMODESMATA (A) THE CYTOPLASMIC CHANNELS OF PLASMODESMATA


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PLASMODESMATA. (A) THE CYTOPLASMIC CHANNELS OF PLASMODESMATA

PIERCE THE PLANT CELL WALL AND CONNECT ALL CELLS IN A PLANT

TOGETHER. (B) EACH PLASMODESMA IS LINED WITH PLASMA MEMBRANE

COMMON TO TWO CONNECTED CELLS. IT USUALLY ALSO CONTAINS A FINE

TUBULAR STRUCTURE(20-40

NM),

THE DESMOTUBULE,

DERIVED FROM

SMOOTH ENDOPLASMIC RETICULUM


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An extension of the smooth endoplasmic

reticulum passes through the pore, leaving a ring

of surrounding cytoplasm through which ions and

small molecules are able to pass freely betweenthe cells.

Extension of endoplasmic reticulum called as

desmotubule

Permits a passage of 10,000 Da Increase conc. of Ca2+ affects permeability,

reverse inhibiting movement of molecules

Molecules like protein, nucleic acids, metabolic

product and plant virus pass throughplasmadesmota also membrane bound molecules


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CHEMICAL SYNAPSES

The term was introduced by British

neurophysiologist Charles Sherrington, whoargued, on the basis of his own observations ofreflex responses and the studies of the greatSpanish anatomist, Ramny Cajal,

Serves as one-way communication devices,

transmitting information in one direction only Consist of pre-synaptic cell which transmits

information to post-synaptic cell which recievesinformation

Pre-synaptic cell and post-synaptic cell are areseparated by minute gap called synaptic cleft

Neurotransmitter act as median fortransmission


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Binding of neurotransmitter molecule produces a

change in the three-dimensional shape of the

receptors that opens a tiny intrinsic pore in the

protein.

Major neurotransmitters:

Amino acids: glutamate, aspartate, D-serine, -

aminobutyric acid (GABA), glycine

Monoamines and other biogenic amines: dopamine

(DA), norepinephrine (noradrenaline; NE, NA),

epinephrine (adrenaline), histamine, serotonin (SE,

5-HT), melatonin

Others: acetylcholine (ACh), adenosine, anandamide,nitric oxide


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SUMMARY What is cell adhesion and its role

Types of cell adhesion Cell adhesion and its molecules (CAM)

integrin, selectin, cadherins and immunglobulin

superfamily

Cell Junctiongap junction, septate junction

anchoring junction (adherens and focal ) and

(desmosomes and hemi-desmosomes)

Gap junction plasmadesmota and chemicalsynapses


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BIBLOGRAPHY

Bruce Alberts, Dennis Bray, Karen Hoplein,

Alexander Johnson, Julian Lewis, Martin Raff,

Keith Roberts and Peter Walter. (2004).

Molecularbiology ofthecell , Ed:4, Garland

science publications, New York,

Geoffery M. Cooper, Robert E. Hausman (2009).The Cell A Molecular Approach, Ed:4, ASM

Press and Sinauer Associates, Inc.

Gerald Karp (2002) Celland Molecular

Biology Conceptand Experiment, Ed: 3,page no: 258-268


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ashish cell adhesion

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