Terence (Receptors and cell signalling) Flashcards
Drug targets
All drugs exert their effect by binding to a target.
Vast majority of targets are proteins.
Some drugs target nucleus acids (less common). Mainly anticancer drugs that interfere with DNA replication.
Anti-acids target proteins.
Predominant protein drug targets for approved drugs are
- Receptors (33%)
- Ion channels (18%)
- Nuclear receptors (16%)
- Kinases (3%)
- Other e.g. enzymes transporters (30%)
Receptor definition in pharmacology
A protein that when bound to a ligand transmits a signal which turns on or off a specific biological/physiological response.
Cell to cell communication
Receptors are important in cell to cell communication.
In a multicellular organism, cells must communicate with other cells to coordinate growth, metabolism, and behaviour.
Communication between cells is mediated mainly by extracellular signalling molecules e.g. hormones, growth factors, cytokines, neurotransmitters
Different types of signalling
Autocrine signalling- signalling molecule release from and binds to the same molecule.
Paracrine signalling- release a signalling molecule which binds to a neighbouring cell.
Endocrine signalling- release a signalling molecule into blood which moves molecule to receptor.
Neurocrine signalling- neurones release neurotransmitters to another neurone or target cell.
Cell surface receptors
All water soluble extracellular ligands including
- all neurotransmitters
- all protein hormones
- all growth factors
A large number of lipid soluble molecules.
There are 1000s of different cell surface receptors.
Different classes of receptors
Cell surface receptor- (ligand doesn’t enter the cell)
- GPCR (metabotropic): ligand binding to receptor activated G-proteins which then activates or inhibits an enzyme or an ion channel
- Ligand gated ion channels (ionotropic): ligand binding to the ion channel causes the opening or closing of the channel and modulates the passage of ions
- Enzyme coupled receptors: ligand binding to the receptor activates the enzyme activity of the receptor or an associated enzyme
Intracellular receptors (nuclear receptors): either cytoplasmic to nucleus
Binding of ligand activates the receptor and alters gene expression.
Lipid soluble so passes through membrane to reach and bind in cytoplasm or nucleus.
Receptors (cell surface)
The endogenous molecule that binds the receptor is called its ligand.
Endogenous ligands include neurotransmitters, growth factors, cytokines, metabolites etc.
Binding of the ligand to the receptor activates the receptor. Binding causes a conformational change of the receptor which changes their function by ‘turning it on’
This initiates a series of events which causes a cellular or physiological response.
Intracellular nuclear receptors
Intracellular nuclear receptors are found in the cytoplasm of the nucleus.
The ligand is usually hydrophobic and is able to pass through the plasma membrane.
Binding of the ligand to the receptor often causes the receptor-ligand complex to enter the nucleus.
The ligand receptor complex acts as a transcription factor and alters gene expression (transcription into mRNA -> leaves nucleus -> mRNA translated into proteins).
Drugs and receptors
Many drugs exert their therapeutic effects by binding to a receptor.
Receptors mediate the actions of pharmacological agonists and antagonists.
Receptors determine the quantitative relationship between dose or concentration of the drug and the pharmacological effects.
Receptors can bind ligands/drugs with relatively high specificity.
Receptors can cause signal amplification and thus receptors can induce a biological response at very low concentrations of ligand/drug (i.e. they are highly efficient).
Receptors as drug targets- agonists
Agonists bind to its receptor and activates the receptor to produce a biological response.
Agonists have affinity (able to bind) and efficacy (generates a response).
Drugs that target receptors often mimic the endogenous ligand.
e.g. Salbutamol is a beta 2 adrenergic receptor agonist (GPCR) used to treat asthma.
Some drugs ARE the endogenous ligand.
e.g. Insulin is an insulin receptor agonist (enzyme linked receptor) used to treat diabetes.
Receptors as drug targets antagonists
Antagonists bind to the the receptor and prevent the agonist from producing the biological response.
Antagonists have affinity (bind to receptor) but do not have efficacy.
- Competitive antagonists- bind to the same site as the agonist (competes for the orthosteric site)
- Non-competitive antagonists bind to an allosteric site (not where the agonist binds) on the receptor to prevent activation of the receptor or bind irreversibly to the agonist binding site.
Beta blockers are antagonists of the beta 1 adrenergic receptor used to treat hypertension.
Tamoxifen binds to the oestrogen receptor used to treat breast cancer.
Cell surface receptors
The majority of drugs that target receptors target cell surface receptors. These include GPCRs, enzyme linked receptors and ligand gated ion channels.
Cell surface receptors are integral membrane proteins (in the membrane- transmit signal from outside to inside).
Some lipophilic and nearly all hydrophilic extracellular ligands bind to cell surface receptors.
When the ligand binds to the receptor a conformational change occurs.
Conformational change initiates a series of intracellular signalling events which causes a cellular/physiological response.
Cell surface receptor structure
Outside- extracellular domain (ligand binding).
Plasma membrane- transmembrane-spanning domain composed of hydrophobic amino acids.
Inside- intracellular domain (transmits signals).
Act as signal transducers i.e. converts an extracellular signal into an intracellular response- important in communicating a message from outside the cell to inside the cell.
Receptor signalling
Receptors transduce an extracellular signal into an intracellular response
- Ligand binds to receptor
- Receptor is activated
- Transmits signal from outside cell to inside cell
- Signal relayed from receptor to effector proteins via signalling pathway
- Effector mediate a response
Important signalling molecules
Signals are often relayed from receptor via
- Protein kinases- when active can phosphorylate proteins and modulate their activity or function.
- GTP-binding proteins or G-proteins- these are molecular switches which can turn on and off signalling pathways by binding to and activating or inhibiting an enzyme or ion channel.
- 2nd messengers- small diffusible signalling molecules that can diffuse away from the site of synthesis and bind to and activate or inhibit proteins- usually an enzyme or ion channel.
- Calcium ions (Ca2+) from the extracellular fluid or from depots within the cell such as the ER and mitochondria. Calcium bind to proteins and regulate their function or activity.
