Source: BIO 311C, Intro to Biology, University of Texas at Austin
Difficulty: Introductory to Intermediate | Prerequisites: Part 1 of these notes (cell signalling fundamentals), basic protein structure and function.
This part covers the first of the three stages of cell signalling: reception. Reception is where the cell detects an incoming signal, and the type of receptor determines everything that follows. You need to know how each receptor class works, what kinds of signals each one handles, and how the binding event transmits information into the cell. Mastering these receptor types is essential for understanding the transduction and response stages covered in Part 3.
Cell signalling follows three stages: reception, transduction, and response. Reception happens when a signalling molecule (ligand) binds a receptor protein, causing it to change shape. There are three main types of cell-surface receptors (GPCRs, receptor tyrosine kinases, and ion channel receptors) plus intracellular receptors for small hydrophobic molecules like steroids. The receptor type determines how the signal enters the cell and what transduction pathway follows.
G protein-coupled receptor (GPCR)
A large family of cell-surface receptors that work with an associated G protein. When a ligand binds, the receptor changes shape, activating the G protein, which then activates downstream enzymes or ion channels.
Think of it as a three-part relay: ligand flips the receptor, receptor flips the G protein, G protein flips the enzyme.
G protein
A signalling protein that acts as a molecular switch, toggling between an inactive (GDP-bound) state and an active (GTP-bound) state.
Receptor tyrosine kinase (RTK)
A cell-surface receptor that, when activated by a ligand, dimerises and phosphorylates tyrosine residues on its own intracellular tail, creating docking sites for relay proteins.
In simple terms, the receptor turns itself into a landing pad for multiple downstream signalling proteins at once.
Ligand-gated ion channel receptor
A cell-surface receptor that opens or closes an ion channel in response to ligand binding, allowing ions to flow across the membrane.
Intracellular receptor
A receptor located inside the cell (cytoplasm or nucleus), activated by small hydrophobic signalling molecules (such as steroid hormones) that can cross the plasma membrane on their own.
Conformational change
A change in the three-dimensional shape of a protein, typically triggered by ligand binding, that alters the protein's activity or its interactions with other molecules.
Dimerisation
The process by which two receptor monomers come together to form a functional pair (dimer), as occurs with receptor tyrosine kinases upon ligand binding.
Every signalling pathway follows the same three-stage sequence:
Reception: the signalling molecule binds to a receptor on or in the target cell.
Transduction: the signal is carried along a pathway of molecular interactions inside the cell (a series of relay steps).
Response: the signal triggers a cellular response, such as a change in gene expression, enzyme activity, or ion channel behaviour.
Reception always involves a conformational change in the receptor protein. Ligand binding alters the receptor's shape, which is what transmits the signal to the next molecule in the chain.
GPCRs are the largest family of cell-surface receptors. They span the membrane seven times (seven-transmembrane-domain structure).
The signalling cycle:
At rest, the G protein sits on the cytoplasmic side of the membrane, bound to GDP (inactive).
A ligand binds the GPCR on the extracellular side, causing a conformational change.
The activated receptor contacts the G protein, causing it to release GDP and bind GTP (active).
The active G protein detaches from the receptor and activates a downstream enzyme (such as adenylyl cyclase).
The G protein's built-in GTPase activity hydrolyses GTP back to GDP, returning the G protein to its inactive state. The system resets.
GPCRs are involved in a vast range of signalling pathways, including those triggered by epinephrine, serotonin, glucagon, and many others.
RTKs are enzyme-linked receptors. Each RTK monomer has an extracellular ligand-binding site, a single transmembrane alpha helix, and an intracellular tail studded with tyrosine residues.
The signalling cycle:
Two RTK monomers sit separately in the membrane (inactive).
A ligand binds, causing the two monomers to come together and form a dimer.
Each monomer phosphorylates the tyrosine residues on the other's intracellular tail (cross-phosphorylation), using ATP.
The phosphorylated tyrosines serve as docking sites for multiple relay proteins simultaneously.
Each docked relay protein can trigger a different downstream pathway, so one RTK activation event can produce multiple cellular responses at once.
This ability to activate several pathways simultaneously makes RTKs particularly important in growth factor signalling.
These receptors are membrane proteins that form a channel. When a specific ligand binds to the receptor's extracellular site, the channel opens (or closes), allowing specific ions to flow across the membrane down their concentration gradient.
The sequence:
Ligand binds the receptor (channel is closed).
Conformational change opens the channel.
Ions (Na⁺, K⁺, Ca²⁺, Cl⁻) flow through.
The resulting change in ion concentration inside the cell triggers a cellular response.
Ligand dissociates, channel returns to its closed conformation.
This type of signalling is central to the nervous system. Neurotransmitters like acetylcholine bind ligand-gated ion channels at synapses.
Some signalling molecules are small and hydrophobic enough to cross the plasma membrane directly, without needing a surface receptor. Steroid hormones (such as estrogen and testosterone) and thyroid hormones work this way.
These molecules pass through the membrane and bind to intracellular receptors in the cytoplasm or nucleus. The activated receptor-hormone complex typically acts as a transcription factor, binding directly to DNA and regulating gene expression.
Because the signal acts directly on gene transcription, intracellular receptor pathways tend to produce slower but longer-lasting responses compared with surface receptor pathways.
Students often think GPCRs and RTKs do the same thing. They do not. GPCRs activate a separate G protein, which then activates enzymes. RTKs are themselves enzymes (kinases) that phosphorylate their own tails to create docking sites.
A common error is thinking that all receptors are on the cell surface. Intracellular receptors exist in the cytoplasm or nucleus and are activated by hydrophobic molecules that cross the membrane directly.
Students sometimes think ligand-gated ion channels are always open and that the ligand closes them. The default state is closed. Ligand binding opens the channel (though some channels work in reverse, this is the standard exam expectation).
Students often confuse phosphorylation (adding a phosphate group, performed by kinases) with dephosphorylation (removing a phosphate group, performed by phosphatases). Both are essential, and the balance between them is what controls the signal.
⚠️ Be able to describe the full GPCR signalling cycle in order: ligand binds, G protein swaps GDP for GTP, G protein activates enzyme, GTP is hydrolysed back to GDP, system resets.
⚠️ RTK dimerisation and cross-phosphorylation is a favourite exam topic. Know that the two monomers phosphorylate each other, not themselves.
⚠️ Know why intracellular receptor pathways produce slower but longer-lasting responses (they act on gene transcription rather than on existing proteins).
⚠️ Be able to classify a signalling scenario by receptor type. If the question mentions steroids or hormones crossing the membrane, think intracellular receptor. If it mentions neurotransmitters at a synapse, think ion channel. If it mentions a G protein, think GPCR.
⚠️ The three stages (reception, transduction, response) are a structuring device for the entire unit. Exam questions often ask you to place a specific molecular event in the correct stage.
True or False: GPCRs have intrinsic kinase activity. (False: they activate a separate G protein. RTKs are the ones with kinase activity.)
Fill in the blank: When two RTK monomers come together after ligand binding, this process is called ______. (dimerisation)
True or False: Steroid hormones bind to receptors on the cell surface. (False: they are hydrophobic and pass through the membrane to bind intracellular receptors.)
Fill in the blank: A G protein is active when it is bound to ______ and inactive when bound to ______. (GTP; GDP)
True or False: Ion channel receptors require a transduction cascade to produce a response. (False: the channel opening is itself the response mechanism; ion flow is immediate.)
Q: Walk through the GPCR signalling cycle, starting from ligand binding and ending with the system returning to its resting state.
A: A ligand binds the GPCR on the extracellular side, causing a conformational change. The activated receptor contacts the associated G protein, causing it to release GDP and bind GTP (becoming active). The active G protein detaches and activates a downstream enzyme (such as adenylyl cyclase). The G protein then hydrolyses GTP back to GDP using its built-in GTPase activity, returning to its inactive state. The receptor, no longer bound by its ligand, also returns to its resting conformation.
Q: How does receptor tyrosine kinase activation differ from GPCR activation?
A: In RTK activation, ligand binding causes two receptor monomers to dimerise. The monomers then cross-phosphorylate each other's intracellular tyrosine residues using ATP. The phosphorylated tyrosines serve as docking sites for multiple relay proteins, allowing the receptor to activate several pathways simultaneously. GPCRs, by contrast, activate a single G protein that then activates a downstream enzyme.
Q: Why can steroid hormones use intracellular receptors when most other signalling molecules cannot?
A: Steroid hormones are small and hydrophobic, so they can pass directly through the lipid bilayer of the plasma membrane. Most other signalling molecules are polar or too large to cross the membrane and therefore require cell-surface receptors.
Q: A patient takes a drug that permanently activates G proteins by preventing GTP hydrolysis. What would happen to the signalling pathway?
A: The G protein would remain permanently active because it could not convert GTP back to GDP. The downstream enzyme (such as adenylyl cyclase) would remain continuously activated, producing an uncontrolled, sustained signalling response. The pathway would not be able to shut off.
Receptor types connect directly to pharmacology and medicine: many drugs work by binding to GPCRs (beta-blockers, antihistamines) or inhibiting RTKs (cancer therapies like imatinib). The intracellular receptor section links back to the membrane permeability concepts from earlier in the course, since the ability of a molecule to cross the membrane determines which receptor class it uses. Understanding ion channel receptors is essential for the nervous system unit, where ligand-gated channels are the primary mechanism at synapses.
GPCR, G protein-coupled receptor, receptor tyrosine kinase, RTK, ion channel receptor, ligand-gated ion channel, intracellular receptor, steroid receptor, conformational change, dimerisation, cross-phosphorylation, GTP, GDP, GTPase, seven-transmembrane receptor, reception, transduction, response, signal transduction pathway, kinase, phosphorylation, BIO 311C, intro biology, UT Austin