Cellular Communication

Cellular receptors are proteins that are essential for cell signalling. When a
signalling molecule (ligand) binds to its matching receptor, it initiates a change in the
receptor. This change triggers downstream signalling actions and changes within the
cell.
There are two main categories of cellular receptors:
Cell surface receptors
Intracellular receptors.
Cell surface receptors
Are located on the cell membrane.
They allow entry to ligands that cannot cross the plasma membrane, which is
often because these ligands are hydrophilic or large.
There are three main types of cell surface receptors:
1. Ion channel receptors act like gates that open to allow ions into the cell.
There are different subtypes of ion channel receptors:
2. Voltage-gated ion channels open or close in response to changes in
membrane potential.
3. Ligand-gated ion channels open or close when a specific ligand, such as a
neurotransmitter, binds to their extracellular domain.
When open, they create a channel for ions to passively enter the cell.
Cellular Communication > GPCRs are a diverse group of cell surface receptors
that use G proteins for cell signalling.
Enzyme-linked receptors have a catalytic site on their intracellular domain. This
site is either associated with an enzyme or has its own enzymatic activity, enabling
it to catalyse chemical reactions.
Cellular Communication > Tyrosine Kinase Receptors are an important subtype of
enzyme-linked receptors.
Dimerisation triggers the phosphorylation of tyrosine molecules on the receptor's
intracellular domain.
Phosphorylated tyrosine molecules are involved in many signalling cascades crucial for
processes like cell division and wound healing.
Intracellular receptors
Are found inside the cell, either in the cytoplasm or nucleus. They bind to ligands
that tend to be small, hydrophobic molecules that can diffuse across the plasma
membrane.
Examples of these ligands include sex hormones, thyroid hormones, and fat-
soluble vitamins (A, D, E, and K).
 Once inside the cell, these ligands bind to their specific intracellular receptor to
form a ligand-receptor complex. This complex binds to DNA in the nucleus,
directly affecting gene transcription and protein synthesis.
Like cell surface receptors, intracellular receptors have three core domains:
1. Ligand-binding domain
2. DNA binding domain
3. Amino terminus (which interacts with the gene transcription machinery)

Clinical relevance of cellular receptors:

Receptor Dysfunction and Cancer: Tyrosine kinase receptors are essential for
growth signalling and cellular differentiation in the body. Dysregulation of tyrosine
kinase signalling is associated with certain cancers.
For example, chronic myeloid leukaemia (CML) is caused by a mutation that
increases tyrosine kinase activity, leading to increased myeloid cell proliferation in
the bone marrow.
Tyrosine kinase inhibitors, such as imatinib, have revolutionised CML treatment
by blocking cancer cell growth while leaving non-mutated cells unharmed.
Viral Entry Into Cells: Viruses can bind to and hijack receptors to gain entry into
cells.
For example, HIV infects CD4 T cells and macrophages by binding to their CD4
receptor. SARS-CoV-2, the virus responsible for COVID-19, enters cells by binding
to angiotensin-converting enzyme 2, a receptor found in the lungs, heart, and
kidneys.

GPCRs
G-protein coupled receptors (GPCRs) are the most significant family of cell
surface receptors. [1]
GPCRs are integral proteins because they span the entire thickness of the cell
membrane. [2]
GPCRs are activated by water-soluble (hydrophilic) hormones that cannot pass
through the cell membrane's lipid bilayer. [1, 2]
Examples of water-soluble hormones include:
Catecholamines (e.g. adrenaline, noradrenaline, dopamine) [3]
Acetylcholine [3]
Glucagon [3]
Serotonin [3]
Secretin [3]
Pituitary hormones (e.g. TSH, ACTH, FSH, LH) [3]
GPCRs link the hormone receptor on the outside of the cell with the enzyme on
the inside of the cell. [2] This linkage enables hydrophilic hormones to exert their
effects within the cell.
The G protein acts as a middle man, connecting the receptor to the enzyme. [2]
G proteins are called guanine nucleotide-binding proteins because they bind to
guanine nucleotides, either GTP or GDP. [3, 4]
The G protein is inactive when bound to GDP. [4]
The G protein is active when bound to GTP. [4]
The enzyme GTPase hydrolyses GTP to GDP, terminating the activity of the G
protein. [4]
G proteins are trimeric proteins, meaning they have three subunits: [4]
Alpha subunit: When the G protein is active, the alpha subunit binds GTP,
dissociates from the beta and gamma subunits, and activates effector molecules.
[4, 5]
Beta subunit and gamma subunit: These subunits form a complex and remain
anchored to the cell membrane. [4]
GPCR activation steps: [4, 5]
1. A water-soluble hormone binds to the receptor on the cell surface.
2. The receptor changes shape (undergoes a conformational change).
3. The activated receptor binds to the G protein.
4. The G protein becomes active and binds GTP instead of GDP.
5. The alpha subunit dissociates and activates effector molecules (either Gq, Gs, or
Gi).
There are three main types of effector molecules: [1, 5]
Gq: Activates phospholipase C, which increases intracellular calcium levels. [6]
Examples of Gq-coupled receptors include: [6]
Alpha-1 adrenergic receptors
M1, M3, and M5 muscarinic receptors
V1 vasopressin receptors
H1 histamine receptors
Gs: Activates adenylate cyclase, which converts ATP to cyclic AMP (cAMP). [6, 7]
cAMP activates protein kinase A. [7]
Examples of Gs-coupled receptors include: [6]
Beta-1, Beta-2, and Beta-3 adrenergic receptors
H2 histamine receptors
V2 vasopressin receptors
Gi: Inhibits adenylate cyclase, leading to decreased cAMP levels. [6]
Examples of Gi-coupled receptors include: [8]
Alpha-2 adrenergic receptors
M2 and M4 muscarinic receptors
Protein kinase A adds a phosphate group to enzymes and other
proteins, activating them. [7] This phosphate group comes from GTP.
[7]
 Phosphatases remove phosphate groups, inactivating enzymes
and other proteins. [7]

Tyrosine Kinase Receptors

These receptors contain kinase, an enzyme that transfers phosphate molecules to the
amino acid tyrosine. When a ligand binds to the extracellular domain of a tyrosine
kinase receptor, the receptor dimerises (pairs) with a neighbouring receptor.
Receptor tyrosine kinases (RTKs) are a type of enzyme-linked receptor found in
the plasma membrane of cells. [1]
RTKs play a crucial role in cell signalling, regulating processes such as cell
growth, differentiation, and survival. [1]
RTKs have an extracellular ligand-binding domain, a transmembrane domain,
and an intracellular catalytic domain. [1]
The extracellular ligand-binding domain binds to specific signalling molecules, such
as growth factors. [1]
The transmembrane domain anchors the receptor in the plasma membrane.
The intracellular catalytic domain possesses tyrosine kinase activity, meaning it can
transfer phosphate groups from ATP to tyrosine residues on target proteins. [1]
RTK activation occurs through a process called dimerization, which is triggered
by ligand binding. [1]

1. Ligand binding: Signalling molecules, such as growth factors, bind to the extracellular
ligand-binding domain of RTKs. [1]
2. Dimerization: Ligand binding causes two RTK monomers to come together and form a
dimer. [1]
3. Autophosphorylation: The dimerization brings the intracellular catalytic domains of
the two RTKs into close proximity, allowing them to phosphorylate each other on
tyrosine residues. [1]
4. Activation of downstream signalling pathways: The phosphorylated tyrosine
residues on the RTK dimer serve as docking sites for intracellular signalling proteins,
leading to the activation of various downstream signalling pathways. [1]