Receptors types

TYPE OF RECEPTORS,THEIR STRUCTURE,MECHANISM.

1. RECEPTORS PRESENTED BY: HEENA PARVEEN, ASST.PROFESSOR, MRCP.

2. The protein targets for drug action on mammalian cells that are described in this chapter can be broadly divided into: Receptors ion channels enzymes carrier molecules (transporters). Receptors Receptors are the sensing elements in the system of chemical communications that coordinates the function of all the different cells in the body, the chemical messengers being the various hormones, transmitters and other mediators Many therapeutically useful drugs act, either as agonists or antagonists, on receptors for known endogenous mediators.

3. Ion channels Some ion channels (known as ligand -gated ion channels or ionotropic receptors ) incorporate a receptor and open only when the receptor is occupied by an agonist; others are gated by different mechanisms, voltage-gated ion channels being particularly important. In general, drugs can affect ion channel function by interacting either with the receptor site of ligand -gated channels, or with other parts of the channel molecule. The interaction can be indirect, involving a G-protein and other intermediaries or direct, where the drug itself binds to the channel protein and alters its function. In the simplest case, exemplified by the action of local anaesthetics on the voltage-gated sodium channel the drug molecule plugs the channel physically blocking ion permeation.

4. Examples of drugs that bind to accessory sites on the channel protein and thereby affect channel gating include: vasodilator drugs of the dihydropyridine type ,which inhibit the opening of L-type calcium channels . benzodiazepine tranquillisers These drugs bind to a region of the GABA receptor-chloride channel complex (a ligand -gated channel), this region being distinct from the GABA binding site. Most benzodiazepines facilitate the opening of the channel by the inhibitory neurotransmitter GABA , but some inverse agonists are known that have the opposite effect, causing anxiety rather than tranquillity . Sulfonylureas used in treating diabetes, which act on ATP-sensitive potassium channels of pancreatic β-cells and thereby enhance insulin secretion.

5. Many drugs are targeted on enzymes . Often, the drug molecule is a substrate analogue that acts as a competitive inhibitor of the enzyme (e.g. captopril , acting on angiotensin -converting enzyme); I n other cases, the binding is irreversible and non-competitive (e.g. aspirin , acting on cyclo-oxygenase ). Drugs may also act as false substrates , where the drug molecule undergoes chemical transformation to form an abnormal product that subverts the normal metabolic pathway. An example is the anticancer drug fluorouracil , which replaces uracil as an intermediate in purine biosynthesis but cannot be converted into thymidylate , thus blocking DNA synthesis and preventing cell division . It should also be mentioned that drugs may require enzymic degradation to convert them from an inactive form, the prodrug , to an active form. D rug toxicity often results from the enzymic conversion of the drug molecule to a reactive metabolite. .

6. RECEPTORS AGONISTS ANTAGONSITS Nicotinic Ach receptor Ach Tubocurarine Nicotine Bungarotoxin Beta- Adrenoceptor Non-adrenaline Propanolol Adrenaline Isoprenaline Histamine Histamine Mepyramie Opiate Mophine Naloxone Dopamine Dopamine Chlorpromazine Oestrogen receptor Ethiylestradiol Tamoxifen

7. ION CHANNELS BLOCKERS MODULATORS Voltage gated sodium channels Local Anaesthetics Veratridine Renal tubule sodium channels Amiloride Aldosterone Voltage gated calcium channels Divalent cations Dihydropyridines ATP-Sensitive K+ channels ATP Sulphonylureas GABA-gated chloride channels Picrotoxin BZD”s

8. The transport of ions and small organic molecules across cell membranes generally requires a carrier protein, because the permeating molecules are often too polar (i.e. insufficiently lipid-soluble) to penetrate lipid membranes on their own. Those responsible for the transport of glucose and amino acids into cells, the transport of ions and many organic molecules by the renal tubule, the transport of Na + and Ca 2+ out of cells, and the uptake of neurotransmitter precursors (such as choline ) or of neurotransmitters themselves (such as noradrenaline , 5-hydroxytryptamine [5-HT], glutamate, and peptides) by nerve terminals. The amine transporters belong to a well-defined structural family, distinct from the corresponding receptors.

9. Type 1: ligand -gated ion channels (also known as ionotropic receptors ). These are membrane proteins with a similar structure to other ion channels, and incorporate a ligand -binding (receptor) site, usually in the extracellular domain. Typically, these are the receptors on which fast neurotransmitters act. Examples include the nicotinic acetylcholine receptor ( nAChR ); GABA A receptor ; and glutamate receptors of the NMDA, AMPA and kainate types.

10. IONOTROPIC RECEPTORS

11. Type 2 : G-protein-coupled receptors (GPCRs). These are also known as metabotropic receptors or 7-transmembrane-spanning ( heptahelical ) receptors . They are membrane receptors that are coupled to intracellular effector systems via a G-protein (see below). They constitute the largest family,and include receptors for many hormones and slow transmitters. for example the muscarinic acetylcholine receptor ( mAChR , adrenergic receptors and chemokine receptors .

12. Type 3: kinase -linked and related receptors . This is a large and heterogeneous group of membrane receptors responding mainly to protein mediators. They comprise an extracellular ligand -binding domain linked to an intracellular domain by a single transmembrane helix. In many cases, the intracellular domain is enzymic in nature (with protein kinase or guanylyl cyclase activity). Type 3 receptors include those for insulin and for various cytokines and growth factors ; the receptor for atrial natriuretic factor is the main example of the guanylyl cyclase type. The two kinds are very similar structurally, even though their transduction mechanisms differ.

13. KINASE-LINKED RECEPTORS

14. Type 4: nuclear receptors . These are receptors that regulate gene transcription. The term nuclear receptors is something of a misnomer, because some are actually located in the cytosol and migrate to the nuclear compartment when a ligand is present. They include receptors for steroid hormones, thyroid hormone , and other agents such as retinoic acid and vitamin D.

15. NUCLEAR RECEPTORS

16. ION CHANNELS Ions are unable to penetrate the lipid bilayer of the cell membrane, and can get across only with the help of membrane-spanning proteins in the form of channels or transporters. The concept of ion channels was developed more than 50 years ago on the basis of electrophysiological studies on the mechanism of membrane excitation. Electrophysiology, particularly the voltage clamp technique remains an essential tool for studying the physiological and pharmacological properties of ion channels.

17. Voltage Gated Sodium Channels

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