Extracellular messengers

(must be recognised by the target cells and therefore require receptors). Extracellular messengers travel in: - Bloodstream - Synapse - Extracellular matrix around a cell

1) Hormones Secreted by endocrine glands Carried in the bloodstream to target tissues E.g. Insulin secreted from Islets of Langerhans in the pancreas 2) Neurotransmitters Secreted by neurones to conduct nerve impulses across a synapse E.g. Acetylcholine 3) Local chemical mediators May be produced by specialised or non-specialised cells Affect other cells in the local environment Works in local vicinity E.g. Histamine secreted by mast cells (A cell filled with basophil granules, found in connective tissue and releasing histamine during inflammatory and allergic reactions).

Receptors
Receptors present in the target tissue should be specific for a given extracellular messenger. They should be tissue specific. Either present on cell surface or may be intracellular (depends on type of extracellular messenger). Chemical messenger reacts specifically with a receptor protein. Binding molecule (referred to as a ligand) could be a: - Drug - Toxin Ligand could be an agonist or antagonist The receptor is a protein with a distinct 3D shape. Therefore interaction between receptor and ligand is specific.

Ligand-receptor complex is held by non-covalent bonds (e.g. Hydrogen, vdw and ionic bonds). Therefore the binding is reversible. No chemical reaction between ligand and its receptor, therefore there is no change in the chemistry of the ligand. Binding of an extracellular chemical messenger to a receptor changes the conformation of the receptor.

Two types of receptors:

- Ionotropic Ionotropic receptors are multimers made of atleast four or five subunits. They contain two functional domains: an extracellular site that binds to neurotransmitters and a membrane spanning domain that forms an ion channel. When a neurotransmitter/ligand binds the receptor becomes activated and ions can flow through the channel.

- Metabotropic Metabotropic receptors do not have ion channels. They affect other channels by activating intermediate molecules called G-proteins. They are therefore called G-protein-coupled receptors. Metabotropic receptors have two domains an: extracellular domain and an intracellular domain. The extracellular domain has a neurotransmitter binding site, whereas the intracellular domain binds to G-proteins. The G protein has three subunits: alpha, beta and gamma. The alpha subunit either binds to GDP or GTP.

Receptor families
Ligand-Gated Ion Channels G-protein Coupled Receptors Tyrosine Kinase Receptors DNA binding Receptors

1) Ligand-Gated Ion Channels These receptors mediate fast synaptic transmission. At chemical synapses these receptors are found on the post synaptic membrane. The binding of a neurotransmitter causes an electrical signal to be produced.

These receptors contain multiple subunits (quaternary protein structure) and each subunit spans the membrane FOUR times. Each single channel has TWENTY membrane spanning helices. One helix from each subunit (M2) lines the channel and is kinked halfway down. This forms a constriction or gate that closes the channel in the resting state. In the resting state: channel is closed

Eg. Nicotinic ACh receptor Found in the post synaptic membrane of the neuromuscular junction The receptor consists of FIVE subunits: o 2 o o o Two molecules of ACh bind to the extracellular binding sites of the two subunits. Both are required in order to elicit a response. When Ach binds, this causes a conformational change in the subunits. The kinked -helices straighten out or swing way. This causes a change in shape of the other subunits. This causes the opening of the channel pore. The M2 helices are rich in negatively charged amino acids which causes an influx of sodium ions. This depolarises the cell and generates an action potential. The subunits are arranged so that they surround a central aqueous channel or pore.

Acetylcholine binds Na+ or Ca2+ pass This causes depolarization in the membrane Normally Ach is lowered by AChE However if abnormally remain high, there is conformational change. Desensitization

Time scale Example

Very fast - Milliseconds Nicotinic ACh receptor GABAA receptor (similar structure to that
of the Nicotinic Ach receptor. GABA binds to synapses in the brain. The binding of GABA to the receptor is inhibitory. It causes the opening of ion channels allowing an influx of chloride ions to hyperpolarise the membrane. The membrane potential is decreased and usually becomes hyperpolarised).

DNA- binding Receptors