Cell Communication: Receptors and Signaling Pathways

Compare and contrast ion-channel-coupled receptors, G-protein-coupled receptors, and enzyme-coupled receptors, explaining how they function.
Explain how the examples given for each receptor lead to its specific cellular signaling.
Explain the basic model for GTP signaling and protein phosphorylation.

Extracellular Signal Molecule: Binds to a receptor protein.
Receptor Protein: Initiates intracellular signaling.
Intracellular Signaling Molecules: Relay the signal.
Effector Proteins: Mediate the cell's response.
- Metabolic Enzyme: Alters metabolism.
- Cytoskeletal Protein: Changes cell shape or movement.
- Transcription Regulator: Modifies gene expression.
Target-Cell Responses: Altered metabolism, shape, movement, or gene expression.

Act as both a receptor for signal molecules and a channel for specific ions.
Open or close in response to signal molecules, converting chemical signals into electric signals.
This type of cell signaling is the simplest and most direct, and is especially important in the nervous system.

Transmembrane proteins with 7-pass transmembrane domains.
Signal molecule binding to the receptor results in a conformational change, triggering signal transduction.
Several varieties of G-proteins exist, each with its own set of receptors and target enzymes.

Act as molecular switches to transduce signals.
Switching from GDP to GTP changes its conformation and activity.
The effect is reversed by hydrolysis of GTP to GDP, terminating signal transduction.

G-protein (GTP binding protein) is a trimeric protein that can bind GDP (off) or GTP (on), acting as the molecular switch.
A signal molecule activates the receptor, which recruits and activates a G protein by replacing GDP with GTP.
GTP binding causes dissociation of the $α$ and $βγ$ subunits and activation.
The activated $α$ subunit (or $βγ$ subunits) activates the next component in the signaling pathway, leading to the generation of intracellular messenger molecules, which induce cellular responses.

Binding of the neurotransmitter acetylcholine to its GPCR on heart cells activates a G protein.
The activated $βγ$ complex opens a $K^+$ channel in the plasma membrane, increasing its permeability to $K^+$ , making the membrane harder to activate and slowing the heart rate.
- The activated $α$ subunit inhibits the enzyme adenylyl cyclase (adenylyl cyclase makes the secondary messenger cAMP).
Inactivation of the $α$ subunit by hydrolysis of its bound GTP returns the G protein to its inactive state, allowing the $K^+$ channel to close.

This process leads to the slowing down of heart rate.

The receptor itself is an enzyme, with three major parts:
- An extracellular domain that interacts with the signal molecule (ligand).
- A transmembrane domain that anchors the receptor.
- An intracellular domain that has enzyme activity.
Example: Tyrosine-kinase receptors, which have tyrosine kinase activity (phosphorylating protein at tyrosine).

Phosphorylation of a protein changes its charge (increases negativity), thus altering its activity.
Phosphorylation acts as a switch to regulate protein function.
Its effect is reversed by dephosphorylation through a phosphatase.

What amino acids are phosphorylated? Serine, Threonine and Tyrosine.

Binding of a signal molecule induces dimerization, which stimulates the receptor kinase activity.
Dimerized receptors phosphorylate each other on tyrosine residues.
Phosphorylation recruits and activates the next components of the pathway.

Insulin binds to the insulin receptor and activates the tyrosine-kinase. The activated tyrosine kinase receptor phosphorylates IRS-1.
IRS-1 activates PI 3-kinase. PI-3 phosphorylates PIP2, converting it to PIP3.
PIP3 binds to and activates the kinase Akt.
Akt phosphorylates proteins, causing activation of glycogen synthase and recruitment of the glucose transporter GLUT4 to the membrane.

Insulin increases glucose uptake into adipose cells, cardiac cells, and skeletal muscle cells.
In Type 2 diabetes, defective plasma membrane expression of GLUT4 hinders glucose entrance into cells.

G-protein coupled receptors activate G proteins by reducing the strength of GDP binding to the G protein, resulting in rapid dissociation of bound GDP, which is then replaced by GTP (present in much higher concentrations). What consequences would result from a mutation in the $α$ subunit of a G protein that caused its affinity for GDP to be reduced without significantly changing its affinity for GTP?
A researcher creates two mutant forms of Protein X (a Tyrosine Kinase Receptor). Mutant 1 lacks its extracellular domain, and mutant 2 lacks its intracellular domain. What would be the cellular consequence of expressing these different mutants in cells that also express normal Protein X?