Receptor subtypes

A receptor is a molecule that receives chemical signal from outside the cell to cause a particular action.

There are four main types in the body.

  1. Ligand gated ion channel
  2. G protein coupled receptor
  3. Tyrosine kinase
  4. Intranuclear

Ligand gated ion channels

These are widespread throughout the body. In general these are pentameric ion pores composed of five subunits, each unit traverses the membrane four times. The binding of a particular ligand changes the channel’s permeability to particular ions, which can then flow down a concentration gradient.

ligandgatedionchannel

Nicotinic acetylcholine receptor

nicotinic

This is a non-selective cation channel, though it is mainly sodium that passes through it when open. These receptors are found at the neuromuscular junction and are important for transmission of action potentials to cause muscle contraction.

The five subunits are: two alpha, one beta, one epsilon and one gamma. Binding of acetylcholine causes opening of the ion pore and increased membrane permeability to sodium. Sodium enters the cell down it’s concentration gradient which causes depolarisation of the muscle sarcolemma and contraction. These receptors are targeted by muscle relaxants used during tracheal intubation and anaesthesia.

GABAa receptor

GABAa

Gamma-amino-butyric acid receptors are widespread throughout the central nervous system. They are pentameric ion channels with two alpha, two beta and one gamma subunits. The two main binding sites are the general anaesthetic binding sites located between the alpha and beta subunits and the benzodiazepine binding site located between the alpha and gamma subunits.

When GABA binds to the receptor the central chloride channel is opened, increasing the membranes permeability to chloride. Chloride enters the cell down a concentration gradient. This reduces the membrane potential and increases the stimulus required to reach a threshold to depolarise the nerve cell. Therefore these receptors have an inhibitory effect on the central nervous system.

G protein coupled receptors

These consist of a single polypeptide chain which crosses the membrane seven times, they are often described as serpentine because of this. The polypeptide has two ends; a C (carboxy) end which is in the cytoplasm and an N (amino) end which is outside the cell and the site of ligand binding.

Common examples of these in the body are the adrenoceptors (alpha and beta), muscarinic acetylcholine receptors and GABAb receptors.

gpcr

The binding of a ligand to the N- end of the polypeptide chain causes a conformational change of the protein. This change causes G protein to dissociate into it’s subunits, and it is the alpha subunit that causes an effect. It is known as G protein because in order to dissociate it binds GTP.

There are three subtypes of the G protein coupled receptor; Gs, Gi and Gq.

Gs e.g. Beta-1 adrenoceptor

Gs

Gs causes stimulation of adenylate cyclase to increase cyclic AMP production. This increases calcium release from the sarcoplasmic reticulum of the myocyte, which has positive chronotropic and inotropic activity. Review the cardiac myocyte structure and function here.

Gi e.g. Muscarinic acetylcholine receptor

Essentially the opposite of Gs, they decrease activation of adenylate cyclase which reduces levels of cyclic AMP within the cell.

Gq e.g. Alpha-1 adrenoceptor

Gq

Gq receptors cause the activation of phospholipase C. This increases levels of mediators such as IP3 and DAG which lead to increase calcium entry into the cell. This promotes smooth muscle contraction in the vessel wall and leads to vasoconstriction.

Tyrosine Kinase

tyrosinekinase

Examples of this type of receptor are the insulin receptors, as well as receptors for cytokines and growth hormone. The ligand binds to the receptor which is related to tyrosine kinase within the cytoplasm. Activation of tyrosine kinase causes a cascade of a variety of processes that are crucial to normal cell function, e.g. gene transcription.

Intranuclear

intranuclear

These receptors are within the nucleus of the cell. The ligand therefore has to be lipid soluble in order to be able to get into the cell nucleus. The ligand binds to the receptors which then have a direct effect on target genes increasing or decreasing protein synthesis. An example of these would by thyroxine and steroids.

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Actions of adrenoceptors

Receptor Subtype Location Action when stimulated
Alpha 1 Vascular smooth muscle Vasconstriction
2 Throughout CNS Sedation, analgesia, decreased sympathetic outflow
Beta 1 Heart Positive inotropy and chronotropy
Platelets Platelet aggregation
2 Bronchi Bronchodilation
Uterus Uterine relaxation, tocolysis
Vascular smooth muscle Vasodilatation
Dopamine 1 Within CNS Modulates extrapyramidal activity
Peripherally Vasodilation of renal and mesenteric vasculature
2 Within CNS Decreased pituitary gland secretion, in particular prolactin
Peripherally Inhibits further noradrenaline release

Catecholamine synthesis

Catecholamines are based on a benzene ring structure with various amine side groups attached at C1 position. When a hydroxyl group is present at C3 and C4 the agent is known as a catecholamine because 3,4-dihydroxybenzene is known as ‘catechol’.

catecholamine

 

Neurotransmitters within the ANS

Pre-ganglionic Post-ganglionic
PNS Acetylcholine Acetylcholine
SNS Acetylcholine Noradrenaline
Adrenal medulla Acetylcholine
Sweat glands Acetylcholine Acetylcholine

The adrenal medulla receives presynaptic fibres from the SNS that synapse directly with the chromaffin cells using acetylcholine as a neurotransmitter. This releases adrenaline and noradrenaline into the circulation which act as hormones rather than neurotransmitters.

Sympathetic nervous system

Consists of pre- and post-ganglionic fibres.

Pre-ganglionic

Lateral horns of spinal cord at thoracic and upper lumbar levels (T1-L2).

Pass into the anterior primary rami and via the white rami communicantes into the sympathetic chain or ganglia. Then they either synapse at that or an adjacent level or pass anteriorly through a splanchnic nerve to synapse in a prevertebral ganglion.

The unmyelinated post-ganglionic fibres then pass into the grey rami communicantes and into the adjacent spinal nerve.

Post-ganglionic

Longer nerves arising from synapses in the sympathetic trunk or sympathetic plexi. Neurotransmitter commonly noradrenaline (except sweat glands which are acetylcholine).

Parasympathetic nervous system

Made up of pre- and post-ganglionic fibres.

Pre-ganglionic

Arise from two locations:

Cranial nerves III, VII, IV and X

  • III – Oculomotor: Iris sphincter muscle (Edinger-Westphal nucleus, III nerve, synapse in ciliary ganglion then enter eye through short ciliary nerves), Levator palpebrae superioris
  • VII – Facial: Lacrimal glands
  • IX – Glossopharyngeal: Salivary glands
  • X – Vagus: Heart, lungs and gut

Sacral fibres S2, 3 and 4)

  • Distal bowel, bladder and genitals

Post-ganglionic

Fibres synapse within ganglia that are close to or within the effector organ.

Post-ganglionic neurone releases acetylcholine which acts via nicotinic receptors.

Parasympathetic nervous system may be modulated by anticholinergics or anticholinesterases.