The role of the receptor
- These are Globular proteins
- Located mostly in the cell membrane
- Receive messages from chemical messengers coming from other cells (CNS)
- Transmit a message into the cell leading to a cellular effect
- Different receptors specific for different chemical messengers
- Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers
- Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve.
- Usually short lived and responsible for messages between individual cells
- Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body
Note: Chemical messengers ‘switch on’ receptors without undergoing a reaction
- Receptors contain a binding site (hollow or cleft on the receptor surface) that is recognised by the chemical messenger
- Binding of the messenger involves intermolecular bonds
- Binding results in an induced fit of the receptor protein
- Change in receptor shape results in a ‘domino’ effect
- Domino effect is known as signal transduction, leading to a chemical signal being received inside the cell
- Chemical messenger does not enter the cell. It departs the receptor unchanged and is not permanently bound
The Binding Site
- A hydrophobic hollow or cleft on the receptor surface – equivalent to the active site of an enzyme
- Accepts and binds a chemical messenger
- Contains amino acids which bind the messenger
- No reaction or catalysis takes place
- Binding site is nearly the correct shape for the messenger
- Binding alters the shape of the receptor (induced fit)
- Altered receptor shape leads to further effects – signal transduction
- Binding interactions must be strong enough to hold the messenger sufficiently long for signal transduction t o take place Interactions must be weak enough to allow the messenger to depart Implies a fine balance Designing molecules with stronger binding interactions results in drugs that block the binding site – antagonists
Main Types of Receptor
- ION CHANNEL RECEPTORS
- G-PROTEIN-COUPLED RECEPTORS
- KINASE-LINKED RECEPTORS
- INTRACELLULAR RECEPTORS
Ion Channel Receptors
- Receptor protein is part of an ion channel protein complex
- Receptor binds a messenger leading to an induced fit
- Ion channel is opened or closed
- Ion channels are specific for specific ions (Na+, Ca2+, Cl–, K+)
- Ions flow across cell membrane down concentration gradient
- Polarized or depolarized nerve membranes
- Activates or deactivates enzyme catalyzed reactions within cell
- Chemical messenger binds to receptor binding site
- Induced fit results in further conformational changes
- TM2 segments rotate to open central pore
- Fast response measured in msec
- Ideal for transmission between nerves
- Binding of messenger leads directly to ion flows across cell membrane
- Ion flow = secondary effect (signal transduction)
- Ion concentration within cell alters
- Leads to variation in cell chemistry
G Protein–Coupled Receptors
- That Activate or Inhibit Adenylyl Cyclase
- the very large group of cell surface receptors that are coupled to signal-transducing trimeric G proteins.
- All G protein–coupled receptors (GPCRs) contain seven membrane-spanning regions with their N-terminal segment on the exoplasmic face and their C-terminal segment on the cytosolic face of the plasma membrane .
- The GPCR family includes receptors for numerous hormones and neurotransmitters, light activated receptors (rhodopsins) in the eye, and literally thousands of odorant receptors in the mammalian nose.
- The signal-transducing G proteins contain three subunits designated α , β, and ϒ. During intracellular signaling the β and ϒ subunits remain bound together and are usually referred to as the Gβϒ subunit. The Gα subunit is a GTPase
- switch protein that alternates between an active (on) state with bound GTP and an inactive (off) state with bound GDP.
- Stimulation of a coupled receptor causes activation of the G protein, which in turn modulates the activity of an associated effector protein.
- Although the effector protein most commonly is activated by Gα ·GTP, in some cases it is inhibited. Moreover, depending on the cell and ligand,
- the Gβϒ subunit, rather than Gα·GTP, may transduce the signal to the effector protein.
- In addition, the activity of several different effector proteins is controlled by different GPCR-ligand complexes.
- All effector proteins, however, are either membrane-bound ion channels or enzymes that catalyze formation of second messengers (e.g., cAMP, DAG, and IP3).
- These variations on the theme of GPCR signaling arise because multiple G proteins are encoded in eukaryotic genomes.
- The human genome, for example, encodes 27 different Gα, 5 Gβ, and 13 Gϒ subunits. So far as is known, the different Gβϒ subunits function similarly.
Bacteriorhodopsin & Rhodopsin Family
- Rhodopsin = visual receptor
- Many common receptors belong to this same family
- Implications for drug selectivity depending on similarity (evolution)
- Membrane bound receptors difficult to crystallize
- X-Ray structure of bacteriorhodopsin solved – bacterial protein similar to rhodopsin
- Bacteriorhodopsin structure used as ‘template’ for other receptors
- Construct model receptors based on template and amino acid sequence
- Leads to model binding sites for drug design
- Crystal structures for rhodopsin and b2-adrenergic receptors now solved – better templates
Tyrosine kinase – linked receptors
- Bifunctional receptor / enzyme
- Activated by hormones
- Protein serves a dual role – receptor plus enzyme
- The receptor binds messenger leading to an induced fit
- Protein changes shape and opens active site
- The reaction catalyzed within cell
- Overexpression related to several cancers
Epidermal growth factor receptor (EGF- R)
- Active site on one half of dimer catalyzes phosphorylation of Tyr residues on other half
- Dimerisation of receptor is crucial
- Phosphorylated regions act as binding sites for further proteins and enzymes
- Results in activation of signaling proteins and enzymes
- Message carried into cell
- Chemical messengers must cross the cell membrane
- Chemical messengers must be hydrophobic
- Example-steroids and steroid receptors
Cyclic ADP-ribose (cADPR),
- The receptor (which may be composed of four subunits) leads to the opening of Ca2+ channels and an influx of Ca2+ in to the cytoplasm from the vacuole and the ER
ETR1 –ETHYLENE RECEPTOR 1
- The ethylene(G) regulates ripening, germination, elongation, senescence, and pathogen responses.
- ETR1, a 79-kDa protein
- ETR1 exists as a dimer in the plasma membrane.
- Ethylene joins the two monomers together and permits intermolecular phosphorylation.
- Mutations in ETR1 (designated efr1) lead to loss of physiological sensitivity to ethylene.
Auxin-binding protein (ABP1)
- Growth regulator
- Functions in cell division and expansion.
- Phytochrome is a photoreceptor, a pigment that plants and some bacteria and fungi use to detect light.
- It is sensitive to light in the red and far -red region of the visible spectrum
- In other word a blue green pigment found in many plant in which it regulates various development processes.
- The long day plant is flower after short exposure to red light the red light is absorbed by phytochrome 660 nm which converts to P730 nm and induces flowering.
- Short day plants absorb light p730 which is converted to p660nm. This is a much slover and needs a long dark period.