11.2 Membrane receptors and signal transduction

Types and Functions of Membrane Receptors

Membrane receptors sit in the plasma membrane and detect extracellular signals like hormones, growth factors, and neurotransmitters. They convert those signals into intracellular responses, making them the starting point for nearly every signal transduction pathway you'll study. Three major receptor families show up repeatedly in cell biology: GPCRs, receptor tyrosine kinases, and ion channel receptors.

Types of membrane receptors

G protein-coupled receptors (GPCRs)

• The largest family of membrane receptors, with well-known examples like rhodopsin (vision) and $\beta$-adrenergic receptors (fight-or-flight response)
• Characterized by seven transmembrane domains that thread back and forth across the plasma membrane
• Coupled to heterotrimeric G proteins on the intracellular side of the membrane

Receptor tyrosine kinases (RTKs)

• Single-pass transmembrane proteins that dimerize (pair up) when a ligand binds
• Possess intrinsic tyrosine kinase activity in their cytoplasmic domain, which is activated by dimerization
• Bind growth factors (e.g., epidermal growth factor), hormones (e.g., insulin), and cytokines (e.g., interferons)

Ion channel receptors

• Transmembrane proteins that form a pore, allowing specific ions to flow across the membrane
• Can be ligand-gated (e.g., the acetylcholine receptor at neuromuscular junctions) or voltage-gated (e.g., sodium channels in neurons)
• Allow rapid ion flux in response to neurotransmitters or changes in membrane potential, which is why they're central to fast processes like synaptic transmission

Structure and function of receptors

G protein-coupled receptors (GPCRs)

• Structure: Seven transmembrane $\alpha$-helical domains. The extracellular N-terminus binds ligands, while the intracellular C-terminus interacts with G proteins.
• Function: When a ligand (hormone, neurotransmitter, odorant) binds, the receptor changes shape and activates its associated G protein. That G protein then modulates effector proteins like adenylyl cyclase (which produces the second messenger cAMP) or ion channels (like potassium channels).

Receptor tyrosine kinases (RTKs)

• Structure: An extracellular ligand-binding domain, a single transmembrane domain, and a cytoplasmic tyrosine kinase domain containing multiple tyrosine residues.
• Function: Ligand binding causes two receptor monomers to dimerize. Dimerization triggers autophosphorylation, where each kinase domain phosphorylates tyrosine residues on the other receptor. Those phosphorylated tyrosines then serve as docking sites for downstream signaling proteins that contain SH2 or PTB domains.

Ion channel receptors

• Structure: Transmembrane proteins with a central pore for ion passage.
  • Ligand-gated: Binding of a specific ligand (e.g., GABA, glycine, acetylcholine) causes a conformational change that opens the channel.
  • Voltage-gated: Changes in membrane potential move voltage-sensing domains within the protein, triggering the channel to open or close.
• Function: Rapidly alter membrane potential or intracellular ion concentrations. This speed is what makes them essential for fast synaptic transmission and muscle contraction.

Signal Transduction and Intracellular Responses

Process of signal transduction

Signal transduction is how cells convert an extracellular signal into an intracellular response, such as a change in metabolism or gene expression. A molecular relay carries the signal from the receptor at the cell surface to targets deep inside the cell.

The process follows four key steps:

1. Reception: A ligand binds to the extracellular domain of a membrane receptor.
2. Transduction: The receptor undergoes a conformational change, which activates intracellular signaling molecules (G proteins, kinases, or second messengers).
3. Amplification: Each activated molecule in the cascade can activate many copies of the next molecule downstream. For example, one activated G protein can stimulate adenylyl cyclase to produce hundreds of cAMP molecules, each of which activates protein kinase A. This is how a single hormone molecule can trigger a massive cellular response.
4. Response: Effector proteins at the end of the cascade carry out the actual change. These might be transcription factors that turn on genes, or metabolic enzymes that shift the cell's biochemistry.

This cascade structure gives cells two advantages: amplification (a small signal produces a large effect) and regulation (the signal can be fine-tuned or shut off at multiple points).

Protein modifications in signaling

Phosphorylation is the most common protein modification in signal transduction. It's the addition of a phosphate group (from ATP) to serine, threonine, or tyrosine residues on a protein, catalyzed by enzymes called protein kinases.

What phosphorylation does to a protein:

• Alters conformation and activity by changing the protein's shape, which can switch it on or off
• Creates docking sites for other signaling proteins (particularly those with SH2 or PTB domains)
• Changes protein localization, such as triggering a transcription factor to move from the cytoplasm into the nucleus

Kinases and phosphatases work as opposing forces. Kinases (like MAP kinases or receptor tyrosine kinases) add phosphate groups to activate signaling. Phosphatases (like protein tyrosine phosphatases) remove them, terminating the signal and restoring the cell to its baseline state.

Signaling cascades typically involve a chain of phosphorylation events: one kinase phosphorylates and activates the next kinase, which phosphorylates and activates the next, and so on. This sequential design allows for both signal amplification (each kinase activates many copies of its target) and signal integration (multiple pathways can converge on or branch from the same kinase). Dephosphorylation by phosphatases is just as important as phosphorylation itself, because without it, signaling would never turn off and the cell would lose homeostasis.