AP Biology 4.1-4.2: Cell Communication

Intercellular signaling

Communication between cells, usually through chemical signals called ligands that bind specific receptors on target cells.

Intracellular signaling

Communication occurring within a cell after a receptor or intracellular signaling protein has been activated.

Ligand

A signaling molecule that binds specifically to a receptor. Binding can change the receptor's conformation and initiate a cellular response.

Target cell

A cell that responds to a particular chemical signal because it contains the receptor that binds that ligand.

Why does a ligand usually affect only certain cells?

Only cells with a receptor whose structure is complementary to the ligand can bind it and respond. Cells lacking that receptor are generally unaffected.

Paracrine signaling

Local signaling in which a ligand diffuses through the extracellular space or matrix to affect nearby cells. Responses are usually rapid and short-lived.

How do cells terminate or localize a paracrine signal?

The ligand can be enzymatically degraded or removed by neighboring cells. This limits its range and restores a concentration gradient for subsequent diffusion.

Why are synaptic signals rapid and localized?

Neurotransmitters diffuse across a very small synaptic gap, approximately $20$–$40\ \text{nm}$. Rapid degradation or reuptake then terminates the signal and allows the postsynaptic cell to respond again.

Endocrine signaling

Long-distance signaling in which endocrine cells release hormones into the bloodstream. Hormones generally act more slowly and persist longer than paracrine signals.

How do hormones differ from paracrine ligands in transport and concentration?

Hormones travel through the bloodstream over long distances and become relatively dilute. Paracrine ligands diffuse locally and can reach higher concentrations near their target cells.

Autocrine signaling

Signaling in which a cell releases a ligand that binds receptors on the same cell or on nearby cells of the same type. It can regulate development, inflammation, pain, and programmed cell death.

Direct signaling through gap junctions or plasmodesmata

Adjacent animal cells can communicate through gap junctions, while plant cells use plasmodesmata. These channels allow small ions and molecules to pass directly between cells.

What can pass through gap junctions, and what is excluded?

Small ions and molecules, including $\mathrm{Ca^{2+}}$, can pass through the channels. Large molecules such as proteins and DNA cannot.

How does direct signaling through gap junctions coordinate neighboring cells?

Small intracellular mediators pass directly between adjacent cells, allowing a group of cells to coordinate its response to a signal received by one cell.

Steroid hormone

A hydrophobic lipid ligand with a characteristic four-fused-ring carbon skeleton. Steroid hormones such as estradiol and testosterone cross the plasma membrane and commonly bind internal receptors.

Examples of hydrophobic ligands

Steroid hormones, thyroid hormones, and vitamin D are hydrophobic ligands that can cross the plasma membrane. Cholesterol is a membrane component and precursor for many steroid hormones.

Why must hydrophobic hormones associate with carrier proteins in blood?

Blood is aqueous, so hydrophobic molecules have low solubility in it. Carrier proteins provide a compatible environment for transport through the bloodstream.

Examples of water-soluble ligands

Water-soluble ligands include ions, small polar molecules, peptides, and proteins. They generally bind the extracellular domains of cell-surface receptors because they cannot cross the membrane's hydrophobic interior unaided.

How does nitric oxide signal despite being a gas?

Nitric oxide, $\mathrm{NO}$, is small and sufficiently membrane-permeable to diffuse across plasma membranes. It acts locally, including by causing smooth muscle relaxation, and has a short half-life.

Why does nitric oxide act over short distances?

Its half-life is very short, so it is rapidly removed or chemically degraded. As a result, its concentration falls quickly with distance from the signaling cell.

How can releasing nitric oxide improve blood flow?

Nitric oxide relaxes smooth muscle in blood vessel walls, causing vasodilation. The resulting increase in vessel diameter can improve blood flow.

Internal receptor

A receptor located in the cytoplasm or another intracellular region. It commonly binds a small hydrophobic ligand that can cross the plasma membrane.

Cell-surface receptor

An integral membrane protein that binds an extracellular ligand and converts that external signal into an intracellular response through signal transduction.

How does ligand polarity determine receptor location?

Small hydrophobic ligands can diffuse through the nonpolar interior of the phospholipid bilayer and bind internal receptors. Polar, water-soluble ligands generally cannot cross the membrane unaided and therefore bind cell-surface receptors.

How do internal receptors regulate gene expression?

After a hydrophobic ligand binds, the receptor changes conformation and may expose a DNA-binding site. The ligand–receptor complex can enter the nucleus, bind regulatory DNA sequences, and alter transcription.

What is the relationship between transcription and protein production in ligand signaling?

Transcription copies DNA information into mRNA. The mRNA then associates with ribosomes, which use its sequence to assemble amino acids into a protein.

Three stages of signal transduction

Reception occurs when a ligand binds its receptor. Transduction converts the received signal into an intracellular relay or signaling cascade. Response is the resulting cellular change, such as altered enzyme activity, gene expression, secretion, movement, or cell division.

Reception

The first stage of cell signaling, in which a signaling molecule binds to a specific receptor on or in a target cell. Binding changes the receptor's activity or conformation.

Transduction

The stage of signaling in which receptor activation is relayed through intracellular proteins, enzymes, second messengers, or phosphorylation events.

Cellular response

The final stage of signal transduction, in which the cell changes its activity in response to the signal. Responses can include altered metabolism, gene expression, secretion, movement, growth, or division.

Signal transduction

The process by which binding of an extracellular ligand to a cell-surface receptor produces an intracellular signal and ultimately a cellular response.

Three structural domains of a cell-surface receptor

The extracellular domain binds the ligand, the transmembrane domain spans the hydrophobic membrane interior, and the intracellular domain interacts with signaling proteins or enzymes.

Why are transmembrane domains rich in hydrophobic amino acids?

They interact favorably with the nonpolar hydrocarbon tails in the phospholipid bilayer. In a channel receptor, amino acids facing the pore are typically hydrophilic so ions or water can pass.

How can ligand binding activate a receptor without entering the cell?

Ligand binding changes the receptor's conformation. That structural change can propagate through the transmembrane region and activate the receptor's intracellular domain or an associated protein.

Receptor dimerization

The joining of two receptor molecules into a stable dimer after ligand binding. Dimerization can bring intracellular domains close enough to activate one another.

Ion channel-linked receptor

A cell-surface receptor that opens or closes a membrane channel in response to ligand binding, allowing specific ions such as $\mathrm{Na^+}$ or $\mathrm{Ca^{2+}}$ to cross the membrane.

How does an ion channel-linked receptor produce a cellular response?

Ligand binding causes a conformational change that opens the channel. Ion movement changes the cell's ion concentrations or membrane potential, producing a response.

G-protein-linked receptor

A cell-surface receptor, typically containing seven transmembrane domains, that activates a heterotrimeric G protein. The activated G protein can regulate an ion channel or an enzyme.

G-protein activation cycle

Ligand binding promotes exchange of GDP for GTP on the $\alpha$ subunit. The $\alpha$ subunit separates from the $\beta\gamma$ complex and regulates downstream targets; hydrolysis of GTP to GDP and inorganic phosphate terminates the signal and allows reassociation.

What is the role of GTP hydrolysis in G-protein signaling?

GTP hydrolysis converts the active $\alpha$ subunit into its GDP-bound inactive form. This provides a built-in mechanism for terminating the signal.

What would happen if a signaling G protein could no longer hydrolyze GTP?

The G protein would remain active for an abnormally long time, causing persistent activation of downstream effectors and potentially an excessive or uncontrolled cellular response.

How can a pathogen disrupt signaling through a G-protein pathway?

A toxin may chemically modify a G protein so that it remains active or inactive inappropriately. For example, persistent activation of an intestinal ion-channel pathway can cause excessive ion and water loss.

Enzyme-linked receptor

A cell-surface receptor whose intracellular domain is itself an enzyme or is directly associated with one. Ligand binding activates the enzyme and initiates a downstream signaling pathway.

Receptor tyrosine kinase (RTK)

An enzyme-linked receptor that transfers phosphate groups from ATP to tyrosine residues on proteins. Ligand binding commonly causes two RTKs to dimerize, followed by autophosphorylation of their intracellular domains.

What sequence of events commonly activates a receptor tyrosine kinase?

A ligand binds extracellular domains, two receptor molecules dimerize, and intracellular tyrosine residues are phosphorylated. These phosphotyrosines recruit or activate downstream signaling proteins.

Autophosphorylation

Addition of phosphate groups to tyrosine residues on the intracellular domains of activated receptor tyrosine kinases. The phosphorylated residues serve as docking or activation sites for downstream signaling proteins.

Why can abnormal receptor tyrosine kinase activity promote cancer?

If an RTK remains active without appropriate ligand binding, it can continuously stimulate pathways controlling growth and division. Persistent downstream signaling may cause uncontrolled cell proliferation.

Signaling pathway or signaling cascade

A series of molecular interactions in which activated proteins, enzymes, and second messengers activate successive downstream components, ultimately producing a cellular response.

Upstream versus downstream signaling events

Events occurring before a specified step in a pathway are upstream; events occurring afterward are downstream. A mutation or drug acting upstream can affect every dependent downstream response.

Second messenger

A small intracellular signaling molecule or ion that relays and often amplifies a signal initiated by a cell-surface receptor. Calcium ions are one example of an intracellular mediator.

How can a signaling cascade amplify a weak extracellular signal?

One activated receptor-associated enzyme can activate many copies of the next signaling component. Repeated activation at successive steps allows a small initial signal to produce a large cellular response.

Signal integration

The convergence of signals from two or more receptors or pathways onto a common cellular response. Integration can require multiple external conditions to be satisfied before the cell responds.

Why can the same ligand cause different responses in different cell types?

Different cell types may express different receptors, signaling proteins, enzymes, or downstream targets. Consequently, the same initial signal can activate different pathways or endpoints.

Phosphorylation

A chemical modification in which a phosphate group, $\mathrm{PO_4^{3-}}$, is added to a molecule. In signaling, kinases commonly phosphorylate proteins on serine, threonine, or tyrosine residues.

What molecular reaction commonly supplies phosphate during protein phosphorylation?

A kinase transfers the terminal phosphate of ATP to a substrate protein, producing ADP. The added phosphate changes the substrate's properties and can regulate its activity.

How does phosphorylation transmit information through a signaling pathway?

Adding a phosphate can change a protein's conformation, activity, localization, or binding interactions. The modified protein can then activate or recruit the next component of the pathway.

Kinase versus phosphatase

A kinase transfers a phosphate group, often from ATP, to a substrate. A phosphatase removes a phosphate group, helping deactivate a phosphorylated signaling protein or receptor.