Cell Communication

Key terms

Ligand - any molecule that binds to a receptor to start a signalling response

Intracrine - The signal stays inside the cell, so the ligand acts inside the same cell.

AA derivative - Amino-acid derivative

Glutamate - the main excitatory neurotransmitter in the brain.

Glutamine - A storage form; remove a group and you get glutamate.

GABA - Main inhibitory neurotransmitter.

Thyroglobulin - a giant protein stored in the thyroid follicle.

Iodinated - iodine atoms added

Catecholamines - tyrosine‑derived neurotransmitters involved in stress, alertness, and movement.

Indolamines - tryptophan‑derived neurotransmitters involved in mood and sleep.

Phenylalanine - essential amino acid used to make proteins and important brain chemicals.

Arachidonic Acid - A fatty acid stored in cell membranes

Eicosanoids - inflammatory signalling molecules

Pregnenolone - steroid hormone made from cholesterol that acts as a precursor for many other hormones, including progesterone, cortisol, testosterone, and oestrogen.

Inactive precursor - a molecule that is produced in an inactive form and must be modified before it can become biologically active

Cell Signalling

Autocrine

  • the cell signal to itself

  • the cell releases ligand which binds to receptors on the same cell

  • helps with self-regulation, feedback loops and immune cells use this a lot


Juxtracrine

  • The signalling cell and target cell must be physically touching

  • this is done with membrane-bound ligands, gap junctions and cell-cell contact


Paracrine

  • The ligand diffuses through the extracellular space to local neighbouring cell

  • growth factors, neurotransmitters and inflammatory signals.


Endocrine Signalling

  • Long-distance signalling

  • hormones into the bloodstream, and they travel to far away target cells.


Different distances = different speeds, strengths, and purposes.

  • Autocrine/intracrine → fast self‑control

  • Juxtacrine → precise, contact‑dependent control

  • Paracrine → local coordination

  • Endocrine → whole‑body regulation


Nucleotides

Nucleotides aren’t just DNA/RNA building blocks — they also act as signalling molecules inside cells.


ATP

ATP in neurotransmission

  • Neurons release ATP as a neurotransmitter.

  • it binds to purinergic receptors (P2X, P2Y) on other neurons or glial cells.

  • Helps regulate pain, inflammation, and synaptic communication.

ATP in immune response

  • Immune cells release ATP when stressed or damaged.

  • ATP acts as a danger signal.

  • Activates immune cells (e.g., macrophages) through P2 receptors.


ADP

  • Regulates blood clotting

  • ADP is produced by platelets during injury

How it works

  • Platelets release ADP which binds to P2Y12 receptors on other platelets.

  • This causes more platelets to stick together → clot formation.


cAMP

  • second messenger

  • cAMP is made for ATP and adenylate cyclase

What it does

  • Acts as a second messenger inside cells

  • Activates PKA (protein kinase A).

  • Controls metabolism, gene expression, hormone responses.


GDP/GTP

  • Nucleotides control G-protein activity, which is central to GPCR signalling.

How it works:

  • G‑protein is inactive when bound to GDP.

  • When a ligand binds a GPCR, GDP is swapped for GTP.

  • GTP activates the G‑protein → triggers downstream signalling.

  • GTP is then hydrolysed back to GDP → turns the signal off.

AA Derivative - Neurotransmitters

AA derivative - a molecule that starts off as an amino acid, but is then converted into something else with a different biological role.


Neurotransmitters Glutamate and GABA are made from amino acids derivatives


Transamination of 2‑oxoglutarate → Glutamate

  • 2‑oxoglutarate is a TCA cycle intermediate.

  • An enzyme adds an amino group (NH₃⁺) to it.

  • This converts it into glutamate.


Deamination of Glutamine → Glutamate

Glutamine is basically glutamate with an extra NH₂ group.

  • Removing that NH₂ group (deamination)

  • Converts glutamine → glutamate


Making GABA from Glutamate

Decarboxylation of Glutamate → GABA

  • Glutamate has a carboxyl group (COOH).

  • Removing that group = decarboxylation.

  • This produces GABA.


The “GABA shunt”

  • This is a small metabolic pathway where:

    • GABA is broken down

    • Intermediates feed back into the TCA cycle


  • Why this matters:
    It links neurotransmitter recycling with cellular energy metabolism.


AA Derivative - thyroid hormones

Tyrosine

  • Thyroid hormones are AA derivatives - as they come from the amino acid Tyrosine.

  • The tyrosine used here is not free tyrosine floating in the cell.

  • It is built into the structure of thyroglobulin, a giant protein stored in the thyroid follicle.


Iodination

  • inside thyroglobulin, tyrosine residues get iodinated

    • MIT - mono-iodotyrosine

      • Tyrosine + 1 iodine

    • DIT = Di-iodothyronine

      • Tyrosine + 2 iodine’s


Coupling reactions - T3 & T4

MIT and DIT combine to form the actual thyroid hormones:


T₃ (Triiodothyronine)

  • Made from DIT + MIT

  • Has 3 iodine atoms

  • More biologically active


T₄ (Thyroxine)

  • Made from DIT + DIT

  • Has 4 iodine atoms

  • More stable, acts as a reservoir


T₃ and T₄ are the active hormones

These hormones regulate:

  • metabolism

  • growth

  • temperature

  • heart rate

  • development


T₃ is the stronger hormone.
T₄ is the storage form that can be converted to T₃ when needed.


Mono-Amines

Amino acids can be turned into neurotransmitters through a series of chemical modifications.


There are 2 types:

  • Catecholamines

  • Indolamines


Catecholamines

  • Made from phenylalanine / Tyrosine

    • dopamine

    • noradrenaline

    • adrenaline


Process

  1. Phenylalanine is converted into tyrosine by adding an –OH group.

  2. Tyrosine gets another –OH group added to the ring → becomes DOPA.

  3. This is the rate‑limiting step in catecholamine synthesis.

  4. Remove a CO₂ group → you get dopamine.

  5. Add an –OH group to dopamine → becomes noradrenaline.

  6. Add a methyl group (CH₃) → becomes adrenaline.


Phenylalanine
→ Tyrosine
→ DOPA
→ Dopamine
→ Noradrenaline
→ Adrenaline


Each step is just:

  • oxidation

  • decarboxylation

  • oxidation

  • methylation



Indolamines

  • Made from tryptophan

    • serotonin

    • melatonin


Process

  • Tryptophan is modified into serotonin through hydroxylation + decarboxylation.

  • Serotonin is then acetylated + methylated in the pineal gland to make melatonin.


Polypeptides

Largest group of signalling molecules
• From small peptides (bradykinin: 9 AA) to large proteins

(Somatotropin /HGH:191 AA)
• Cannot cross cell membranes


Eicosanoids - Fatty acids

Arachidonic acid (AA) — a fatty acid stored in cell membranes — is converted into eicosanoids, which are powerful inflammatory signalling molecules.


There are two main pathways:

  1. COX pathway → prostaglandins, prostacyclin, thromboxane

  2. LOX pathway → leukotrienes


Arachidonic acid (AA)

  • AA sits inside membrane phospholipids.

  • When a cell is activated (injury, infection, inflammation)

  • enzymes release AA:

    • Phospholipase A₂

    • Phospholipase C


COX pathway (Cyclooxygenases) → Prostaglandins & Thromboxane

  • COX‑1 and COX‑2 convert AA into PGH₂, the key precursor.

  • PGH₂ then becomes:

    • Prostaglandins (PGD₂, PGE₂, PGF₂α)

      • Pain

      • Fever

      • Vasodilation

      • Uterine contraction

    • Prostacyclin (PGI₂)

      • Vasodilation

      • Inhibits platelet aggregation

    • Thromboxane (TXA₂)

      • Platelet activation

      • Vasoconstriction

      • Clot formation


LOX pathway (Lipoxygenases) → Leukotrienes

  • Lipoxygenase (especially 5‑LOX) converts AA into HPETE, which becomes leukotrienes.

  • Leukotrienes (LTB₄, LTC₄, LTD₄, LTE₄)

Functions:

  • Bronchoconstriction

  • Asthma

  • Allergy

  • Neutrophil recruitment

  • Strong inflammatory signalling


Steroid Hormones

Cleavage of cholesterol to pregnenolone

  • CYP enzymes to obtain other steroids


Corticosteroids: Glucocorticoids, Mineralocorticoids
Sex Steroids: Oestrogens, Androgens, progestogens


Signalling molecules - Storage & transport

Hormones/ long distance signalling: prepro or pro-hormone forms


Preprohormone

  • The inactive precursor produced directly by ribosomes.

  • Contains a signal peptide that directs it into the rough endoplasmic reticulum (RER).

  • The signal peptide is removed to form a prohormone.


Prohormone

  • Still inactive or only weakly active.

  • Undergoes further processing (e.g., cleavage by enzymes) in the Golgi apparatus or secretory vesicles.

  • Converted into the active hormone before or after secretion.


Carrier proteins: globulin and serum albumin


SIGNALLING MOLECULES - STORAGE AND TRANSPORT
Short distance signalling:
Stored in vesicles and released as active molecules


Signalling molecules - Inactivation

Essential to prevent excessive cell stimulation and allow the cell to react to new signals


• Peptides/proteins are degraded through peptidases
• Steroid hormones are degraded by CYP450 enzymes
• Eicosanoids are often degraded locally
• Neurotransmitters are recycled back into pre-synaptic vesicles or are degraded by enzymes


Signalling Receptors

All receptors are proteins and are grouped into 4 major classes

  • Ion channels

  • GPCRs (G-Protein- Coupled Receptors)

  • Receptor Tyrosine
    Kinases/Phosphatases

  • Intracellular receptors


Receptor Specificity

Agonists activate a receptor response
• endogenous (hormones)
• or exogenous (drugs)

Antagonists block a receptor response
• inhibitor/drugs


Receptors sensitivity and saturability

Affinity constant: Kd
• concentration when 50% receptors are occupied with
ligand
• When all receptor sites are occupied, the cell will be maximally simulated and the
system is saturated
• The cell can over/under-express the receptor to alter its Kd


SIGNAL TRANSDUCTION

  • Two-step process:
    • 1: Change of shape of the receptor bound by ligand
    • 2: Downstream molecular events in the cell cytoplasm


LIGAND-GATED ION CHANNELS

Structure: a ligand binding domain and an ion channel
• Leads to change of membrane polarity
• Ethanol affects many ion-gated channels in the brain!


GPCRS

Complex regulation involving multiple membrane bound proteins that migrate when the ligand is bound to the extracellular domain
• Transduction: change in cytosolic concentration of 2nd diffusible messengers: cAMP, IP3, DAG, Ca2+

RECEPTOR TYROSINE KINASES/PHOSPHATASES


RTKs
• Phosphorylation of the tyrosine residues
• Tyr-P acts as a signal to recruit and activate other cytosolic proteins, which generate metabolic changes (often through SH2/3 domains of the
target proteins)
• Receptor tyrosine phosphatases (RPTPs ) are less common

CYTOSOLIC/NUCLEAR RECEPTORS

Bind to lipid-soluble molecules like steroid hormones, thyroid hormones, vitamin D, and retinoic acid


Class I: in the cytoplasm, HSP released upon activation, translocate
to the nucleus

  • Glucocorticoid /Mineralocorticoid receptors,
    Estrogen / Androgen / Progesterone receptors


Class II: In the nucleus, heterodimers with RXR receptors

  • TR receptors

  • vitamin D receptors

  • RAR receptors