AP Syllabus focus:
‘G protein–coupled receptors are important eukaryotic receptors that activate intracellular signaling cascades when ligands bind.’
G protein–coupled receptors (GPCRs) are a major class of eukaryotic membrane receptors that translate an external ligand-binding event into intracellular activity. They illustrate how receptor shape changes can launch multi-step signaling inside cells.
Overview of G protein–coupled receptors (GPCRs)
GPCRs are plasma-membrane proteins that detect many types of extracellular signals (ligands) and convert them into intracellular signals by activating G proteins, which then regulate downstream targets.
G protein–coupled receptor (GPCR): A cell-surface receptor with seven transmembrane regions that, upon ligand binding, changes shape and activates an intracellular G protein to start a signaling cascade.
A key idea for AP Biology is that ligand binding does not usually “open” the receptor like a channel; instead, binding causes a conformational change that enables the receptor to interact with intracellular proteins.
Core components in a GPCR pathway
The receptor and ligand
Ligand: a specific signaling molecule that binds the receptor’s extracellular region.
Specificity: receptor structure determines which ligand can bind and trigger signaling.
The G protein (signal relay)
Most GPCR pathways use a heterotrimeric G protein (three-subunit complex) located on the cytoplasmic side of the membrane.
Heterotrimeric G protein: A three-part (α, β, γ) membrane-associated protein that switches between inactive (GDP-bound) and active (GTP-bound) states to transmit signals from an activated GPCR to intracellular targets.
The GTP/GDP cycle is central: the G protein is “off” with GDP and “on” with GTP.
GPCR signaling depends on a nucleotide-controlled switch in the heterotrimeric G protein. This diagram summarizes the GDP→GTP exchange on the α subunit, separation into α-GTP and βγ, effector regulation, and GTP hydrolysis that returns the system to the inactive heterotrimer. Source
Effector proteins and responses
Activated G proteins regulate effector proteins, which can include:
Enzymes that generate intracellular signaling molecules (often called second messengers)
Ion channels whose opening/closing changes cell behavior
Other proteins that trigger broader intracellular signaling cascades
Step-by-step: how ligand binding activates an intracellular cascade
1) Ligand binding and receptor activation
A ligand binds the GPCR on the extracellular side.
The GPCR changes shape, exposing/creating a binding interface for the G protein on the cytoplasmic side.
2) GDP-to-GTP exchange (turning the G protein on)
The activated GPCR binds the inactive G protein (αβγ with GDP on α).
The GPCR promotes GDP release from the α subunit.
GTP binds to α (because GTP is abundant in the cytosol), switching the G protein “on.”
3) Subunit separation and effector activation
The G protein splits into:
α-GTP
βγ dimer
Either α-GTP and/or βγ can bind an effector protein.
Effector activation initiates an intracellular signaling cascade that can spread the signal through multiple molecular steps.
4) Producing cellular changes
Depending on the pathway and cell type, GPCR-driven cascades can:
Alter activity of existing enzymes (rapid responses)
Change membrane potential via ion channel regulation
Indirectly influence longer-term changes (for example, through activation of proteins that ultimately affect gene regulation)
Common GPCR effectors (examples of cascade starters)
GPCRs are emphasized as examples because a single receptor event can activate a chain of intracellular events.
Adenylyl cyclase
A classic GPCR effector pathway is the adenylyl cyclase cascade, in which an activated G protein stimulates adenylyl cyclase to convert ATP into the second messenger cAMP. The figure also shows how cAMP activates protein kinase A (PKA), providing a mechanistic example of how one receptor event can be amplified into broad intracellular effects. Source
When activated by certain G proteins, it produces cAMP, which can activate protein targets and propagate signaling.
Phospholipase C (PLC)
Can generate lipid-derived intracellular signals that mobilize cellular responses, often involving calcium release from internal stores.
G protein–regulated ion channels
βγ (or α-GTP) can directly modulate channels, changing ion flow and cell excitability.
The AP-level takeaway is the logic: ligand binding → GPCR shape change → G protein activation → effector control → intracellular cascade → cellular response.
Signal termination and pathway resetting (why signaling is controllable)
GPCR pathways are tightly regulated so cells can respond appropriately and then return to baseline.
Intrinsic GTPase activity of the α subunit hydrolyzes GTP to GDP, turning α “off.”
This promotes reassociation of α (GDP-bound) with βγ, reforming the inactive heterotrimer.
Receptor desensitization
Prolonged stimulation can reduce responsiveness by modifying the receptor and decreasing G protein activation.
Effector/second-messenger removal
Intracellular signaling molecules are often degraded or removed to stop downstream activation.
What makes GPCRs a key AP Biology example
Eukaryotic importance: GPCRs are widespread in animal, plant, and fungal signaling and underlie many physiological responses.
Amplifying cascades: activation of effectors can trigger multi-step intracellular signaling, allowing small external signals to produce strong internal effects.
Pathway flexibility: different cells can express different G proteins/effectors, so the same GPCR stimulus can lead to different responses in different tissues.
FAQ
Different GPCRs couple to different G proteins (and different effectors), so the same general mechanism can trigger distinct downstream targets.
Cell-specific expression patterns of G proteins and effectors further diversify outcomes.
Orthosteric ligands bind the primary (natural ligand) binding site.
Allosteric ligands bind elsewhere and change receptor behaviour (e.g., increasing or decreasing responsiveness) without necessarily activating the receptor alone.
Some receptors show basal activity due to spontaneous conformational shifts into an active-like state.
Cells can counterbalance this with regulatory proteins that stabilise inactive receptor states.
Internalisation can reduce signalling by removing receptors from the cell surface.
In some cases, internalised receptors continue signalling from intracellular compartments, changing the timing and location of downstream effects.
Some toxins chemically modify G protein subunits, locking them in active or inactive states.
This disrupts normal GDP/GTP cycling and leads to abnormally persistent or absent signalling.
Practice Questions
Describe how ligand binding to a GPCR leads to activation of a G protein. (2 marks)
Ligand binding causes a conformational change in the GPCR enabling interaction with the G protein. (1)
GPCR promotes GDP release and GTP binding on the α subunit, activating the G protein. (1)
Explain how GPCR activation can produce an intracellular signalling cascade and how the signal is terminated. (5 marks)
Activated GPCR binds inactive heterotrimeric G protein (αβγ) at the membrane. (1)
GDP is exchanged for GTP on α, activating the G protein. (1)
α-GTP and/or βγ dissociate and bind an effector protein (e.g., enzyme or ion channel). (1)
Effector activation initiates downstream intracellular signalling steps (cascade), leading to a cellular response. (1)
Termination via GTP hydrolysis to GDP on α (intrinsic GTPase), causing reassociation/inactivation. (1)
