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RECEPTORS

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

Neurotransmitters: 

• 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

Hormones: 

• 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

Induced Fit

• 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

1. ION CHANNEL RECEPTORS
2. G-PROTEIN-COUPLED  RECEPTORS
3. KINASE-LINKED  RECEPTORS
4. 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

Gating

• 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

Intracellular receptors

• 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)

• IAA
• Growth regulator
• Functions in cell division and   expansion.

Phytochrome 

• 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.