Cellular Receptors

Cell Surface Receptors

The cell membrane creates a physical barrier that separates the intracellular environment from the extracellular environment. Cell surface receptors span the cell membrane and are called transmembrane or integral proteins. They contain three domains – an extracellular ligand-binding domain, a hydrophobic domain embedded within the plasma membrane, and an intracellular domain.

Cell surface receptors regulate the cell membrane by controlling the entry and exit of ions, catalysing growth and metabolic processes, and responding to chemical messengers and intercellular signals. Ligands which are large, hydrophilic or charged, are generally unable to cross the plasma membrane on their own and must rely on cell surface receptors to facilitate entry.

There are three main types of cell surface receptors: ion channel receptors, G-protein coupled receptors (GPCRs) and enzyme-linked receptors.

Ion Channel Receptors

Ion channel receptors are like gates which open to allow the passive movement of ions down their concentration gradient. Different subtypes exist, including voltage-gated ion channels which open or close in response to changes in membrane potential and mechanically-activated channels which respond to mechanical stimuli such as pressure or stretch.

Ligand-gated ion channels (or ionotropic receptors) open or close in response to the binding of a specific ligand to their extracellular domain. The ligand could be a neurotransmitter, hormone, cytokine or even a drug.

OpenStax (https://commons.wikimedia.org/wiki/File:1216_Ligand-gated_Channels.jpg), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0), via Wikimedia Commons

Fig 1
Diagram showing the function of ligand gated ion channels: Acetylcholine (ACh) is the ligand and when it binds to the cellular receptor, the channel opens to allow ions to move in or out of the cell.

G-protein Coupled Receptors

GPCRs are a diverse group of cell surface receptors that use specific proteins called G proteins to participate in cell signalling. There are a discrete number G proteins associated with GCPRs which have a characterised immediate response within a cell. Their structure and function are discussed in detail in this article.

G_s proteins stimulate the enzyme adenylyl cyclase whilst G_i proteins have an inhibitory effect. G_q or G₁₁ proteins stimulate phospholipase C. The downstream effect of these actions are vast and varied and depend on the specific cell type in which the receptor has been activated.

Enzyme-linked Receptors

Enzyme-linked receptors are cell surface receptors that have a catalytic site on their intracellular domain. They can either be associated with an enzyme or have intrinsic enzymatic activity, enabling them to catalyse chemical reactions.

The binding of a ligand to the extracellular domain leads to activation of the enzyme, triggering a specific intracellular response. An important subtype of enzyme-linked receptors are tyrosine kinase receptors.

Tyrosine kinase receptors have intrinsic kinase activity –  i.e. they can transfer phosphate molecules. When a ligand binds to its extracellular domain, the receptor dimerises with its neighbouring receptor, triggering its kinase activity. The kinase phosphorylates the amino acid tyrosine on the intracellular domain of the receptor.

The kinase in the receptor can also transfer phosphates onto other signalling molecules in the cell, triggering many different signalling cascades such as those involved in cell division, wound healing and glucose homeostasis.

Created in BioRender

Fig 2
Diagram showing tyrosine kinase receptor, an enzyme-linked receptor, triggered by the binding of insulin, which activates a cascade of downstream metabolic responses.

Intracellular (or internal) receptors are found within the cytoplasm or nucleus of the cell. Their ligands tend to be small, hydrophobic (i.e. lipid-soluble) molecules allowing them to freely diffuse across the plasma membrane.

Once inside the cell, these ligands bind to their specific intracellular receptor to form a ligand-receptor complex. This complex binds DNA in the nucleus, directly affecting gene transcription and protein synthesis. The receptor-ligand complex acts as a transcription factor, regulating the transcription of DNA into RNA molecules which can then be translated into proteins.

Like cell surface receptors, intracellular receptors also have three core domains. These comprise a ligand-binding domain, DNA binding domain and an amino terminus (which interacts with the gene transcription machinery).

Examples of ligands which bind to intracellular receptors include steroid hormones (e.g. sex hormones or mineralocorticoids, glucocorticoids), thyroid hormones and fat-soluble vitamins (A, D, E and K).

By CNX OpenStax (https://commons.wikimedia.org/wiki/File:Figure_09_01_03.jpg) [Creative Commons 4.0] (https://creativecommons.org/licenses/by/4.0/), via WikiMedia Commons

Fig 3
Diagram of intracellular receptor action

Below are some examples of of the different types of cellular receptors: