G-protein-coupled receptors are transmembrane proteins that act as molecular switches by converting between on and off states to convert an extracellular signal into an intracellular signal.
Cell-surface receptors, also known as transmembrane receptors, are cell surface, membrane-anchored, or integral proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction, converting an extracellular signal into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Different receptors favor binding to specific ligands in what is known as the “lock and key” model of ligand-receptor interactions. An updated model for ligand-receptor interactions is known as “induced fit” because the receptor and ligand can change shape during an interaction.
Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types. Each cell-surface receptor has three main components: an external ligand-binding domain (extracellular domain), a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The size and extent of each of these domains vary widely, depending on the type of receptor. Cell-surface receptors are involved in most of the signalling in multicellular organisms.
G-protein-coupled receptors, one type of cell-surface receptor, bind an extracellular ligand and activate a membrane protein inside of the cell called a G-protein (guanine nucleotide-binding protein). G-proteins may be monomeric, consisting of only one subunit, or heterotrimeric. Heterotrimeric G proteins have three subunits: α, β, and γ. G-proteins can bind both guanosine triphosphate (GTP) and guanosine diphosphate (GDP). All G-protein-coupled receptors have seven transmembrane domains, but each receptor has its specific extracellular domain and G-protein-binding site.
Cell signalling using G-protein-coupled receptors occurs as a cyclic series of events that switch between on and off states. Before a ligand binds to the receptor to initiate a signal, the inactive G-protein binds to a specific site on the receptor. In this inactive state, the G-protein is associated with GDP. However, once a ligand binds the receptor, the resultant shape change (AKA conformational change) in the receptor activates the G-protein, which releases GDP from the α subunit and picks up GTP. The subunits of the G-protein then split into the α subunit and the β/γ subunits. As a result, one or both of these G-protein fragments may be able to activate other proteins, such as ion channels or enzymes in the membrane. One classic example of an enzyme activated by G-protein-coupled receptors is adenylate cyclase, which produces the second messenger cyclic adenosine monophosphate (AKA cyclic AMP). Later, the GTP on the active α subunit of the G-protein is hydrolyzed to GDP and phosphate, and the β/γ subunits are deactivated. The subunits reassociate to form the inactive G-protein, and the cycle starts over.
Humans have more than 1,000 known different types of GPCRs, and each one is specific to a particular function. GPCRs regulate many biological processes, including the immune system, growth, learning, and mood. There are several diseases associated with the disruption of G protein-coupled receptor signalling, including diabetes, allergies, some cancers, and cardiovascular diseases, and they are the target of around 30 to 50% of all modern medicinal drugs.
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Key Points
• Intracellular receptors are located in the cytoplasm of the cell and are activated by hydrophobic ligand molecules that can pass through the plasma membrane.
• Cell-surface receptors bind to an external ligand molecule and convert an extracellular signal into an intracellular signal.
• Three general categories of cell-surface receptors include G-protein-coupled receptors, gated ion channels, and enzyme-linked receptors.
• G-protein-coupled receptors bind a ligand and activate an intracellular membrane protein called a G-protein, which then interacts with either an ion channel or an enzyme in the membrane. A classic example is the activation of adenylate cyclase to produce cyclic AMP.
• The malfunction of signalling downstream of G-protein coupled receptors is linked to human diseases.
Key Terms
Integral protein: A protein (or assembly of proteins) that is permanently attached to the plasma membrane.
Signal transduction: When a ligand binds to a membrane receptor and initiates a response within the cell, converting that extracellular signal into an intracellular signal.
Guanosine triphosphate (GTP) and guanosine diphosphate (GDP): A molecule that acts as a source of energy for signal transduction events.
Monomeric protein: A protein consisting of a single subunit.
Heterotrimeric protein: A protein consisting of three separate subunits. In the case of heterotrimeric G-proteins, these are the α, β, and γ subunits.
conformational change: A change in the shape or structure of a protein or protein complex.
G-proteins (guanine nucleotide-binding protein): A family of proteins that can act as on and of switches by binding to either GDP or GTP.
G-protein-coupled receptors: transmembrane proteins that act as molecular switches by converting between on and off states to convert an extracellular signal into an intracellular signal
Extracellular: outside the cell
Intracellular: inside the cell
Hydrophobic: avoids water
Adenylate cyclase: produces the second messenger cyclic adenosine monophosphate cAMP
