CELL SIGNALING: Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis

Overview of Cell Signaling 1. Reception: A cell detects a signaling molecule from the outside of the cell. A signal is detected when the chemical signal (also known as a ligand) binds to a receptor protein on the surface of the cell or inside the cell. 2. Signal Transduction: When the signaling molecule binds the receptor it changes the receptor protein in some way. This change initiates the process of transduction. Signal transduction is usually a pathway of several steps. Each relay molecule in the signal transduction pathway changes the next molecule in the pathway. 3. Response: Finally, the signal triggers a specific cellular response.

Cell signaling can be divided into 3 stages:

Agonist and Antagonist: An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance. Whereas an agonist causes an action, an antagonist blocks the action of the agonist. A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses

How do signaling molecules work? Signaling molecules may trigger: an immediate change in the metabolism of the cell (e.g., increased glycogenolysis when a liver cell detects adrenaline); an immediate change in the electrical charge across the plasma membrane (e.g., the source of action potentials); a change in the gene expression — transcription — within the nucleus. (These responses take more time.)

TYPES OF SIGNALING Autocrine Signalling: Signals molecules target the same cell itself. Sometimes autocrine cells can target cells close by if they are the same type of cell as the emitting cell. An example of this are immune cells. Paracrine Signalling: Signals target cells in the vicinity of the emitting cell. Neurotransmitters represent an example. Endocrine signalling: Signals target distant cells. Endocrine cells produce hormones that travel through the blood to reach all parts of the body.

TYPES OF INTRACELLULAR SIGNALLING

RECEPTORS: First to sense a signal Mostly present on plasma membrane Most identified receptors are proteins. ROLE OF RECEPTORS: Must be specific Must bind signaling molecule tightly Must convey fact that signaling molecule has arrived to cell interior

TYPES OF RECEPTORS: Extracellular signaling molecules bind to either : Cell-surface receptors or Intracellular receptors. Most signaling molecules are hydrophilic and are therefore unable to cross the plasma membrane directly; instead, they bind to cell-surface receptors, which in turn generate one or more signals inside the target cell. Intracellular receptors: Some small signaling molecules diffuse across the plasma membrane and bind to receptors inside the target cell either in the cytosol or in the nucleus Many of these small signaling molecules are hydrophobic and nearly insoluble in aqueous solutions; they are therefore transported in the bloodstream and other extracellular fluids bound to carrier proteins, from which they dissociate before entering the target cell.

TYPES OF RECEPTORS:

G-PROTEIN LINKED RECEPTORS G protein coupled receptors (GPCRs), also known as seven-transmembrane domain receptors,, serpentine receptor, and G protein-linked receptors (GPLR), constitute a large protein family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. They are called transmembrane receptors because they pass through the cell membrane, and they are called seven-transmembrane receptors because they pass through the cell membrane seven times

Contains the three domains: 1. Extracellular domain: Binds signal molecule 2. Transmembrane domain: Transmit signal response to cytosolic domain 3. Cytosolic domain: Produces a final response and causes activation of G- protein

G PROTEINS: G proteins also known as guanine nucleotide-binding proteins are a family of proteins involved in transmitting chemical signals originating from outside a cell into the inside of the cell. G proteins function as molecular switches. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they bind GTP, they are 'on', and, when they bind GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.

G protein is an  trimeric protein which binds guanine nucleotides. They can be considered molecular switches wherein…  GDP (inactive)   GTP (active) +  The dissociated  subunit expresses GTPase activity.

G PROTEIN RECEPTORS: G proteins located within the cell are activated by G protein-coupled receptors (GPCRs) that span the cell membrane. Signaling molecules bind to a domain of the GPCR located outside the cell. An intracellular GPCR domain in turn activates a G protein. The G protein activates a cascade of further signaling events that finally results in a change in cell function. G protein-coupled receptor and G proteins working together transmit signals from many hormones, neurotransmitters, and other signaling factors.

G PROTEIN CELL RECEPTOR:

MECHANISM: The ligand binds to a site on the extracellular portion of the receptor. Binding of the ligand to the receptor activates a G protein associated with the cytoplasmic C- terminal. This initiates the production of a "second messenger". The most common of these are cyclic AMP, (cAMP) which is produced by adenylyl cyclase from ATP The second messenger, in turn, initiates a series of intracellular events (shown here as short arrows) such as phosphorylation and activation of enzymes Dephosphorylation of enzymes

In the case of cAMP, these enzymatic changes activate the transcription factor CREB (cAMP response element binding protein) Bound to its response element 5' TGACGTCA 3' in the promoters of genes that are able to respond to the ligand, activated CREB turns on gene transcription. The cell begins to produce the appropriate gene products in response to the signal it had received at its surface. In addition to their roles in affecting gene expression, GPCRs regulate many immediate effects within the cell that do not involve gene expression.

Turning GPCRs Off A cell must also be able to stop responding to a signal. Several mechanisms cooperate in turning GPCRs off. When activated, the Gα subunit of the G protein swaps GDP for GTP. However, the Gα subunit is a GTPase and quickly converts GTP back to GDP restoring the inactive state of the receptor. The receptor itself is phosphorylated by a kinase, which not only reduces the ability of the receptor to respond to its ligand but Recruits a protein, β-arrestin, which further desensitizes the receptor, and triggers the breakdown of the second messengers of the GPCRs.

ENZYME LINKED RECEPTORS: An enzyme-linked receptor also known as a catalytic receptor is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protein possessing both enzymatic catalytic and receptor functions. Like G-protein-linked receptors, enzyme-linked receptors are transmembrane proteins with their ligand-binding domain on the outer surface of the plasma membrane Examples of the enzymatic activity include: Receptor tyrosine kinase, as in fibroblast growth factor receptor. Most enzyme-linked receptors are of this type. Serine/threonine-specific protein kinase, as in bone morphogenetic protein

They have two important domains, an extra-cellular ligand binding domain and an intracellular domain, which has a Catalytic function; and a transmembrane helix. The signaling molecule binds to the receptor outside of the cell and causes a conformational change on the Catalytic function located on the receptor inside of the cell. The internal side of the receptor acts as an enzyme, which is activated when the appropriate ligand binds to the external portion of the receptor. Enzyme-linked receptors only span the membrane once(as opposed to seven times for G-protein-linked receptors)

Enzyme-Linked Receptors Receptor Tyrosine Kinase: receptors for growth factors (Epidermal growth factors) or hormones (insulin) Ligand: large polypeptide endocrine/paracrine; growth factors or differentiation signals – binds with very high affinity Conformational States: 1. Ligand binds, adjacent monomer – Dimerizes 2. Dimerization activates tyr Kinase Domain 3. Criss-cross tyr auto phosphorylation 4. Phosphorylated sites recruit SH2 domain containing protein 5. Signal transduction and cellular response

RECEPTOR TYROSINE KINASE: MECHANISM

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