Biomembrane and Cell signalling BCH 452(V) Cell To Cell Comunication Dr. Samina Hyder Haq Assistant professor Dept of biochemistry Collage of Science King Saud university

Multicellular Communication  Cells must communicate with each other and the extracellular matrix for the benefit of organism.

Gap Junction or Cell to cell Channels They serve as passageways between the interior of two contiguous cells. The width of the gap between them is 35A Small hydrophylic molecule as well as ions can pass through them. Gap junctions are important for intracellular communication. Gap junctions are also important for the nourishment of cells such as bone and lens. Inorganic ions and most metabolites e.g, sugers, amino acids and nucleotides can flow between the interior of cells joined by gap junction. In Contrast Proteins, Nucleic acids and polysaccharides are too large to pass.

A cell to cell channel is made up of 12 molecules of Connexion one of many family of membrane proteins the molecular weight ranges from kD. Each Connexion molecule appear to have four membrane spanning helices. Six Connexion molecule are hexagonally arrayed to form a half channel Connexion or HemiChannel.

Other types of cell junctions Desmosome: binding spots between cells with proteins called cadherins Tight junctions: impermeable ▫E.g. gut tube, doesn’t let enzymes from gut into blood stream Gap junctions: tubes that let small molecules pass between cell.

Cells responds to various extracellular signals. In the absence of signals cells die.

Signal transduction, when one signal is manifested in another form,

Signalling pathways

Forms of intracellular Signalling

Two types of receptors.

Three classes of cell surface receptor.

Ion channel linked receptor. Rapid transmission of signals across synapses in nervous system and of other electrically excitable cells (eg. muscle) Open or close channel for flow of specific types of ions across plasma membrane, which produces electrical current, thereby converting chemical signals into electrical ones.

Types of Ion channel

G-protein Linked receptor. Activate a membrane bound protein G protein Targets of activated G proteins are ion-channels and membrane-bound enzymes. Responses to signal are usually fast (seconds) and reversible.

Heterotrimeric G-protein Present in underside of the cell surface. Heterotrimeric, with α, β and γ subunits. Only  subunit binds guanine nucleotide (GTP or GDP) In non-activated state, α-  subunit has GDP bound

Activation of G-protein Binding of signal molecule to GPCR), causes a conformational change in the receptor that is transmitted to a G-protein on the cytosolic side of the membrane. The nucleotide-binding site on G  becomes more accessible to the cytosol, where [GTP]converts to [GDP]. G  releases GDP & binds GTP

Substitution of GTP for GDP causes another conformational change in G . G  -GTP dissociates from the inhibitory  complex & can now bind to and activate another membrane bound enzyme called adenyl cyclase. Activated target protein

Turning off the signal G  hydrolyzes GTP to GDP + P i. (GTPase). The presence of GDP on G  causes it to rebind to the inhibitory  complex. Adenylate Cyclase is no longer activated. Phosphodiesterases catalyze hydrolysis of cAMP  AMP.

Some G-protein regulates Ion Channel

Enzyme-linked receptor. Are a second major type of Single-span transmembrane proteins with ligand-binding domains on outer surface of plasma membrane. They were recognized initially through their role in responses to extracellular signal proteins that promote the growth, proliferation, differentiation, or survival of cells in animal tissues. These signal proteins are often collectively called growth factors, and they usually act as local mediators at very low concentrations (about M).

Very slow response G-protein coupled receptor E-linked Receptor

Five known classes of receptors (1) receptor tyrosine kinases, (2) tyrosine-kinase-associated receptors, (3) receptor serine/threonine kinases, (4) transmembrane guanylyl cyclases, (5) histidine-kinaseassociated receptors. I

Receptor Tyrosine Kinases Largest class of enzyme-linked receptors. Are often called growth factor receptors because some ligands act as growth factors, which trigger a cell to divide. Cytoplasmic domain functions as tyrosine kinase, phosphorylating a tyrosine amino acid in a protein.

Binding of signal molecule causes two receptor molecules to dimerise. Dimer formation brings the kinase domains into close contact, stimulating kinase activity. Activation of receptor tyrosine kinases - phosphorylation on tyr residues

Activation of receptor tyrosine kinases - assembly of signalling complex. Each phosphorylated tyrosine serves as a specific binding site for different intracellular signal proteins. These proteins become phosphorylated themselves

Some proteins in signalling complex are adaptor proteins. Adaptor proteins dock onto phosphorylated tyrosine on activated receptor. Adaptor recruits and stimulates another signalling protein

The regulation of Ras activity Many receptor tyrosine kinases activate the small GTP-binding protein Ras

Receptor tyrosine kinases signal to Ras

Ras activates a protein kinase cascade Active Ras promotes activation of phosphorylation cascade: Mitogen-activated protein kinase (MAP kinase) cascade or extracellular signal-regulated kinase (ERK) cascade

MAP kinase stimulates changes in target proteins leading to cell division MAP kinase (ERK) phosphorylates various target proteins, including other kinases and gene regulatory proteins that control gene expression

RAS in Cancer Ras protein is mutationally activated in ~ 30% of human cancers. In these cancers, Ras is permanenty switched on, stimulating the cells to divide, even in the absence of extracellular signals.

Cytokine receptor Binds to hormones or local mediator ytokines Have no intrinsic enzyme activity, but are associated with cytoplasmic tyrosine kinases called JAKs (or Janus kinases

Activation of cytokine receptor. Binding of cytokine causes the JAKs to phosphorylate and activate one another. The activated kinases then phosphorylate the receptor on tyrosines.

Gene regulatory proteins called STATs (signal transducers and activators of transcription) present in cytosol attach to phosphorylated tyrosines. The JAKs phosphorylate and activate the STATs.

The activated STATs dissociate from receptor, dimerise and migrate to the nucleus where they activate transcription of specific target genes