Cell Communication & Signaling

Cell Communication

• Extracellular signal molecules activate intracellular signaling pathways in cells
• The signal molecule connects to a receptor protein
• This activates a series of signaling proteins
• Intracellular signaling proteins then interact with a target protein
• This alters the target protein and changes cell behavior

Budding Yeast Cells and Mating Factor

• These cells are normally independent
• They are able to communicate, influencing each other's behavior during sexual mating
• Yeast cells send small peptides to communicate for mating

Extracellular Signal types

• Higher animals use various signal molecules like proteins, peptides, amino acids, nucleotides, steroids, retinoids, fatty acid derivatives, and dissolved gases
• Most signal molecules originate in and are secreted from the signaling cell via exocytosis
• Some are released through diffusion
• Some remain bound to the signaling cell's surface
• Hydrophilic signal molecules can't cross the plasma membrane and bind to cell-surface receptors
• Hydrophobic molecules diffuse across the plasma membrane and bind to receptors inside the cell

Target Cell Response

• It is mediated by a receptor protein, specifically binding the signal molecule and initiating cell response
• Binding of an extracellular signal molecule / ligand to transmembrane receptors activates intracellular signals that change cell behavior

Signal Distances

• Contact-dependent signaling requires direct membrane-membrane contact and is important in development and immune responses
• Paracrine signaling entails signals released into the extracellular space acting locally on neighboring cells
• Paracrine signals use local mediators and are rapidly taken up, destroyed, or immobilized to prevent diffusion
• Synaptic signaling uses neurons to transmit electrical signals along axons releasing neurotransmitters at synapses
• Endocrine signaling depends on endocrine cells secreting hormones into the bloodstream for widespread distribution

Synaptic vs Endocrine Signaling

• Synaptic signaling is faster and more precise than endocrine signaling
• Electrical impulses transmit information faster than diffusion of hormones
• Local neurotransmitters can achieve high concentrations quickly, unlike diluted hormones
• Neurotransmitter receptors have low ligands allowing dissociation to terminate response faster
• Neurotransmitters are quickly removed from the synaptic cleft for precision in time and space

Coordination via Autocrine Signaling

• Production of secreted signals in a group of same / identical cells results in a higher concentration compared to a single cell
• Signal binding to the same cell type receptors leads to a coordinate response
• Autocrine signaling involves a cell secreting signal molecules binding to its own receptors
• Secretion reinforces developmental decisions
• Autocrine signaling allows identical cells to make same developmental decisions
• It underlies the "community effect" in early development when a group of identical cells responds to a differentiation-inducing signal

Gap Signals

• Gap junctions coordinate activities of neighboring cells through gap junctions
• Specialized cell-cell junctions form between closely apposed plasma membranes
• Cytoplasms of joined cells directly connect via narrow water-filled channels
• Small intracellular molecules are exchanged
• Ca2+ and cyclic AMP are exchanged, excluding macromolecules
• Cells connected by them can communicate directly and respond to extracellular signals coordinately

Cell response and extracellular Signals

• Multicellular cells respond to hundreds of signals that are soluble, bound to the ECM, or bound to neighboring cells in millions of combinations
• Cells respond to combinations of signals selectively, responding to one combination by differentiating, to another by multiplying, and yet another by performing functions like contraction / secretion
• Most cells depend on specific signal combinations to survive
• Deprivation of these signals will trigger cell-suicide / apoptosis
• A number of signaling combinations allows animals to control cells in highly specific ways.

Cell Response Varianace

• Specific cell reaction depends on receptor proteins allowing response to a particular subset of signals
• It vanes according to intercellular machinery integrating it
• Single signal molecules produce different effects on different target cells

Acetylcholine

• Neurotransmitter example
• Stimulates contraction in skeletal muscle
• Decreases rate and force of contraction in cardiac muscle

Gas Signals

• Small enough, hydrophobic signal molecules diffusing across target-cell plasma membrane
• Binding to / regulation of specific intercellular protein
• Example: Nitric oxide (NO) is a gas signal in animals and plants that regulates smooth muscle contraction in mammals
• NO local mediator activated by macrophages and neutrophils to promote kill of microorganisms
• Plants use NO in injury defense
• NO gas is made by the deamination of amino acid arginine, catalyzed by NO syntheses
• NO diffuses out and into neighboring cells because it passes readily across membranes
• Acts only locally for 5-10 seconds before converted to nitrates by oxygen and water
• Carbon monoxide(CO) is another act, acting intercellular in the same way as NO stimulation of guanylyl cyclase

Steroid Hormones

• There are a group of small, hydrophobic, nongaseous hormones and local mediators able to enter the cell directly
• Steroid hormones, thyroid hormones, retinoids, and vitamin D can directly pass
• Though structually / functionally different, they bind to cellular receptors that activate the receptors, which interact with DNA modulating transcription
• Receptors are part of the nuclear receptor superfamily, including intercellular receptor proteins
• Many family members found by DNA sequencing only, their ligand is not known, called orphan nuclear receptors

Intercellular Receptor Protein

• Located in cytosol/ nucleus
• They directly regulate gene transcriptions with a binding that induces the transcription of binding to coactivator proteins
• Hormone receptor can normally be found in active form in cells where it has not been stimulated
• The bound receptors create inhibitory protein complexes, where ligand binding will shift receptor proteins and dissociate an inhibitory complex

Transcriptional Response

• The direct activation of specific genes takes ~30mins
• Response is called "primary response"
• Protein products activate secondary, delayed response

Cell-Surface Receptors type classification

• Ion-channel receptors / transmitter gated ion channels / ionotropic receptors are in rapid synaptic signaling between electrically excitable cells.
• Neurotransmitters briefly open/ close the ion channel, the protein changes plasma permeability and excitability.
• The receptors are a large family of homologous transmembrane proteins
• G-Protein linked receptors regulate plasma bound protein (enzyme / ion channel) activity
• Receptor regulation interaction with protein by a trimeric GTP-binding protein / G protein
• Target protein activation will change concentration in mediators or plasma permeability, the intracellular mediators alter additional signaling proteins
• Receptors belong to a family homologous, seven-pass transmembrane proteins
• Enzyme linked receptors either function directly as enzymes or are directly associated with existing enzymes activating them
• Single pass transmembrane proteins bind outside the cell and are catalytic / enzyme binding inside.
• Receptors are protein kinases, binding causes phosphorylation of proteins

Extracellular Matrix

• Animal tissue is contains space
• They play the role of tensile and compressive strength, and elasticity
• ECM buffering in fluid, water control by acting cell surface
• Most of the body is connected tissue is a mix of ECM

ECM Location

• ECM is specialized by location to:
  • Bone (mineral to help compress)
  • Eye (transparent to light)
  • Tendons (elastic)
• Specialized ECM (Basal Lamina) underlies epithelial cells
• Immune defense comes from immune cells
• Fibroblast cells generate tissue such chondroblasts and osteoblasts

ECM Composition

• Mixture of:
  • water
  • structural porteins
  • Collagen, elastin, fibronectin, laminin
  • Carbohydrates
  • Glyocproteins
  • Proteoglycans

Glycosaminoglycans / GAGs

• Polymers of repeated sugars
• Galactose, galactosamine, N-acetylgalactosamine-4-sulfate , galacturonic
• Hyaluronan main GAG
• Released membrane spun
• It is an enormous molecule, almost always unsulfated

Hylauronidan

• Used to add ECM / cell hold and is by hyluronidase removal for cell migration
• A stand alone, not covalently bounded
• Gags negative and charged ion
• Attract positively charged ions, especially with water
• Creates 90% of the ECM volume, with low mass
• Provides compression and bulking

Glycosaminoglycans

• Synthesized intercellularly, sulfated, secreted, covalently bounded
• Made of 20 - 200 residues long
  • Chondroitin
  • Dermatan
  • Heparan
  • Keratan

Types of Proteins and Proteoglycans

• Glycoprotein is small when branched. ER and Golgi will add chains
• Proeoglyan : Decorated proteins containing serine and via acidic synthesis.

ECM Structure

• Aggrecan is found ECM, has core made of chondroitin and keratan
• It is also found binding Hyalunronan, with aggregates that can be as long as bacteria
• Heparan sulfate is polymer

Heparan sulfate proteoglycans (HSPGs)

• It regulates growth factors / binds chemokines activating the Wnt pathway
• Binding of FGF and kinase. Then cell activity increases for proteases.

Collagen

• Largest fibrous proteins
• It is a family with 16 members, tensile to make strength in the matrix 1 and II collagens via fibrils
• They self assemble later
• Collagen cross likining creates stability

Collagen Chains / Synthesis

• Three chains make rope-like structure that fives the molecule tensile structure
• Beginning with systhesis in RER, chain made
• Modification during hydroxyllysines in the Golgi Body through procollagen
• Final step is forming ends in extracellular location

Collagen Structures

• Chain structure oxidizes lysines which bond to the molecules and its chains
• The fiber makes a strait rope
• They all interact to form the matrix

###Collagen, elastin related

• Collagen can be fibril associated by crosslinking, Type IV and VII collagens give a mesh for the basal lamina.Elastin gives flexibility, it crosslinked (elastin precursors)
• Defects from fibrillin can cause Marfan syndrome

###Fibronectin

• Binds cells, and attaches the body by using collagen for vessels, gives "stickiness" (Similar to blood cots / Fibrinogen) - Various domains can be defined where proteolysis occurs - Domains can bind to the integrin itself

###Cell Binding with Fibronection

• RGD disruption prevents cell bonding, detaching it
• Viper venom disintegrin limits fibrogen production

###Basal Lamina

• Specialized ECM containing epithelium, muscle fats and kidneys
• Most is structure for adhesion and migration
• Specialized filters and selective binding of integrin
• All bind integrins and ECM is mostly Gags and proteins

Basement Membrane Composition:

• Laminin
• IV collegen
• Enactin
• Herparan
• Predmoninant GAG

###Lamnin

• 100 mm swordlike beta and gamma shapes sheets link cell with nidogen

###IV type Collegen

• Networks that bind the propeptides for shape

Nidogen

• 150 kDA domell glycoprotein acting with collegen and laminin

Perlacan

• Perlocan is important with a 400kD core that binds chains
• Has cell adhesion and can link vasal lamina, as well disrupting prothrombin for coagulant

ECM Overview

• mesh between layers, with integral transmembrane receptors acting with nidogen

Membrane Composition

• The matrix also contains glycoproteins in cytoplasm and collagen fibers to help adhesion for proteins and carbohydrates

Cellular Adhesion

• Tight juctions are the key for cell adhesion, desmosesomes link cytoskeleton, and gap junctions exchanges compounds . CAMs create junctions, also membrane for lamina

• Hemidesmosomes help with fiber connections to epithelium for protein

Integrins Overview

• Regulation of behavior linked with lower affinity and Ca/Mg
• Connect the cellular matrix
• hetermodimers cell activity on a unit by specific subunits

Cellular Attachments

• Activity to kinase to gene expressions
• BL assembles with kinases to from new matrix
• Acts a factories and helps activate

Immune System

• Expresses a protein to bind with integrins

Inside and out cell Signalling

• Integrins are linked to cells through talin by fiber binding

Cadherins Overview

• Cadherins are cell recognition mediators, these need calcium to fuction