Difficulty: Introductory | Prerequisites: Basic cell biology (membrane structure, proteins, gene expression)
Cells do not operate in isolation. Every multicellular organism depends on cells sending, receiving and responding to chemical signals, a process collectively called cell signalling (or cell-to-cell communication). This topic sits at the intersection of membrane biology, protein biochemistry and gene regulation. You should already be comfortable with the structure of the plasma membrane, the basics of protein shape and function, and how genes are transcribed and translated. Understanding signal reception is the first step: how does a message from outside the cell reach the machinery inside it?
Cells communicate by releasing signal molecules that bind to specific receptors on or inside target cells. Lipid-soluble signals (steroids, thyroid hormones) pass straight through the membrane and bind intracellular receptors, skipping the transduction step entirely. Water-soluble signals bind receptors on the cell surface, triggering internal relay chains.
Signal molecule (ligand)
A chemical released by one cell that binds to a specific receptor on or in another cell, triggering a response. Think of it as the "message" in a postal system: it only matters if it reaches the right address.
Receptor
A protein that recognises and binds a specific signal molecule. Receptors sit either on the cell surface (membrane receptors) or inside the cell (intracellular receptors). In simple terms, the receptor is the lock, and the signal molecule is the key.
Intracellular receptor
A receptor located in the cytoplasm or nucleus. Lipid-soluble signals such as steroid and thyroid hormones reach these by diffusing through the plasma membrane. Think of it as a VIP who bypasses the front desk and walks straight into the office.
G protein-coupled receptor (GPCR)
A membrane receptor that works with a G protein to relay signals. When the signal molecule binds, the receptor activates a G protein on the cytoplasmic side. In simple terms, the receptor flips a molecular switch.
Receptor tyrosine kinase (RTK)
A membrane receptor that, once activated, adds phosphate groups to itself and to other proteins. Binding of the signal molecule causes two receptor molecules to form a dimer. Think of it as a self-starting relay: the receptor phosphorylates itself to kick things off.
Integrins
Transmembrane proteins that connect the extracellular matrix to the cytoskeleton inside the cell. They allow direct communication between the matrix environment and internal cell machinery. In simple terms, integrins let the cell "feel" what is outside it.
Ligand-gated ion channel
A membrane channel that opens when a specific signal molecule (such as a neurotransmitter) binds to it, allowing ions to flow across the membrane. Think of it as a gate that only opens when a particular hand pushes it.
Steroid hormone
A lipid-soluble signal molecule derived from cholesterol (e.g. estrogen, testosterone, cortisol). Because it is hydrophobic, it crosses the plasma membrane without help and binds an intracellular receptor. In simple terms, steroids do not need a doorbell; they walk through the wall.
Transduction
The process of converting an extracellular signal into an intracellular one, usually through a cascade of molecular changes. Lipid-soluble signals skip this step because they enter the cell directly.
Cell communication follows three stages: reception, transduction and response. This document covers reception; transduction and response are in the companion notes.
Reception: a signal molecule binds to a receptor, either at the cell surface or inside the cell.
Transduction: the signal is relayed and often amplified through a chain of molecular events.
Response: the cell changes its behaviour (gene expression, enzyme activity, cell shape, etc.).
Lipid-soluble signals (steroid hormones, thyroid hormones): hydrophobic, so they pass directly through the plasma membrane. They bind intracellular receptors and typically act as transcription factors. Because they enter the cell on their own, they do not require transduction.
Water-soluble signals (neurotransmitters, peptide hormones, growth factors): hydrophilic, so they cannot cross the membrane. They bind membrane receptors on the extracellular surface.
G protein-coupled receptors (GPCRs)
Span the membrane seven times.
On the cytoplasmic side, they interact directly with G proteins.
When the signal molecule binds, the receptor changes shape and activates the G protein by swapping GDP for GTP.
A G protein bound to GTP is in its active state.
The binding site for the signal molecule is on the extracellular side; the receptor itself is embedded in the plasma membrane.
Receptor tyrosine kinases (RTKs)
Binding of the signal molecule causes two receptor molecules to dimerise.
The receptor then catalyses the transfer of a phosphate group to tyrosine residues on itself (autophosphorylation).
The binding site for the signal molecule is on the extracellular side; the receptor is in the plasma membrane.
Ligand-gated ion channels
The signal molecule binds and the channel opens, allowing ions to flow through.
Neurotransmitters are a classic example: a neuron responds to a particular neurotransmitter by opening gated ion channels, meaning the neurotransmitter is serving as a signal molecule.
Binding of the signal molecule allows ions to flow through a channel in the receptor. This is classified as "neither" a GPCR nor an RTK.
Steroid hormones (estrogen, testosterone, cortisol) are lipid-soluble. They diffuse freely through the lipid bilayer and bind receptors in the cytoplasm or nucleus.
The cortisol pathway is a good model:
Cortisol passes through the plasma membrane into the cytoplasm.
Cortisol-receptor complex forms in the cytoplasm.
The complex enters the nucleus, where it binds to genes.
The complex acts as a transcription factor.
The transcribed mRNA is translated into a specific protein.
Estrogen is an extracellular signal molecule that can diffuse through the plasma membrane and bind an intracellular receptor.
Thyroid hormones also bind intracellular receptors.
A hormone like testosterone is lipid-soluble and crosses the membranes of all cells, yet it affects only target cells. The reason: intracellular receptors for testosterone are present only in target cells. The same principle applies to all hormones: the target organ must have receptors that recognise and bind the hormone molecule.
Estrogen can mediate many different effects at puberty because it binds to specific receptors inside many kinds of cells, each with different receptor proteins and different downstream gene targets.
Extracellular matrix components can induce specific gene expression in embryonic tissues. For this direct communication between the matrix and the cell, integrins are the transmembrane proteins most likely involved. They bridge the extracellular matrix and the cytoskeleton, transmitting signals inward.
Cortisol signalling flowchart (memorise this sequence):
Cortisol passes through the plasma membrane into the cytoplasm.
Cortisol binds its receptor in the cytoplasm, forming a cortisol-receptor complex.
The complex enters the nucleus and binds to specific gene sequences.
The complex acts as a transcription factor, switching genes on or off.
The transcribed mRNA is translated into a specific protein.
Note the distractor in the source material: "Cortisol binds to a receptor on the outside of the cell" is incorrect. Cortisol is lipid-soluble and enters the cell first.
GPCR vs RTK comparison (know which features belong to which)
Feature | GPCR | RTK | Both |
|---|---|---|---|
Interacts directly with G proteins | Yes | No | |
Catalyses phosphate transfer to the receptor | No | Yes | |
Binding site on extracellular side | Yes | ||
Receptor in the plasma membrane | Yes |
Antihistamines work by blocking histamine from binding to its GPCR (the H₁ receptor), which is why they reduce allergy and inflammation symptoms. Drugs that block testosterone receptors are used in prostate cancer treatment: if the receptor cannot bind testosterone, the transcription of testosterone-responsive genes decreases. Cortisol-based drugs (corticosteroids) exploit the same intracellular-receptor pathway to regulate inflammation and immune responses.
Students often think steroid hormones bind to receptors on the cell surface. They do not. Steroids are lipid-soluble and pass through the membrane to bind intracellular receptors.
Students sometimes believe that all signals require transduction. Lipid-soluble signals skip transduction entirely because they enter the cell directly.
Students confuse "active G protein" with "G protein bound to GDP." A G protein is active when bound to GTP, not GDP.
Students assume testosterone affects all cells because it can cross all membranes. It only affects cells that express the intracellular receptor for testosterone.
The distinction between lipid-soluble and water-soluble signals is tested repeatedly. Know which type bypasses transduction.
Be able to order the steps of cortisol signalling from membrane crossing to protein synthesis.
GPCR vs RTK comparison questions are common. Memorise which features are unique to each and which are shared.
Questions about why a hormone affects only certain cells come up often. The answer always centres on receptor presence in target cells.
Integrin questions test whether you know that direct matrix-to-cell communication requires a transmembrane link, not a soluble signal.
True or false: A steroid hormone requires a membrane receptor to enter the cell. (False)
Fill in the blank: A G protein is active when bound to ____. (GTP)
True or false: Lipid-soluble signals require transduction. (False)
Fill in the blank: The transmembrane proteins that link the extracellular matrix to the cytoskeleton are called ____. (Integrins)
True or false: Testosterone affects all cells it contacts because it can cross any membrane. (False)
Q: A drug inhibits the cellular response to testosterone. What is the most likely effect on the cell?
A: The transcription of certain testosterone-responsive genes would decrease.
Q: How do steroid hormones gain access to their intracellular receptors?
A: They are lipid-soluble, so they diffuse freely through the lipid bilayer of the plasma membrane.
Q: Which type of intercellular signal would be processed without transduction?
A: A lipid-soluble signal, because it enters the cell directly and binds an intracellular receptor.
Q: Extracellular matrix components induce gene expression in embryonic tissues. Which transmembrane protein is most likely involved?
A: Integrins, because they physically connect the extracellular matrix to intracellular signalling pathways.
Q: A neuron responds to a neurotransmitter by opening gated ion channels. What role is the neurotransmitter playing?
A: It is serving as a signal molecule (ligand) that binds a ligand-gated ion channel.
Q: Estrogen mediates many different effects across different tissues at puberty. How is this possible with a single hormone?
A: Estrogen binds to specific receptors inside many kinds of cells, each with different receptor proteins and different downstream gene targets.
This material connects directly to membrane structure (Chapter on membranes): the lipid bilayer's hydrophobic core is why steroids can diffuse in but peptide hormones cannot. It also ties into gene expression and regulation: intracellular receptors for steroids act as transcription factors, linking signal reception straight to the topics of transcription and translation. The companion notes on signal transduction and response (Part 2) pick up where reception leaves off.
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