Receptors are split in to what are known as four super families. It is these four main families that are believed to provide the majority of information regarding the effects of several drugs. The families are grouped based on the different types of cellular effects they obtain. Some occur within milliseconds, having a rapid response whereas others operate at a much slower rate, taking place over hours and even days in cases such as the effects produced by steroid or thyroid hormones (which will be discussed further in detail). The more complex of the families is G-protein coupled receptors also known as metabotropic. The simplest is ligand-gated ion channels also known as ionotropic receptors followed by kinase-linked and nuclear receptors.
The G-protein coupled receptors are monomers composed of seven transmembrane helices, where their main role is to transmit signals into the cell itself. They bind both endogenous as well as exogenous ligands such as nucleotides, photons lipids and peptides. They do this by combining a ligand from their extra-cellular surface to a guanine-nucleotide binding protein on an intracellular surface. They are also known as being metabotropic receptors which suggests that they encourage metabolic changes to take place in postsynaptic cells. G-protein coupled receptors form the largest family out of the four mentioned above, consisting of receptors for numerous hormones as well as slow transmitters. They are able to respond to a wide range of agonists which consist of amines, neurotransmitters, hormones and proteins.. In this family of receptors the G-protein is activated as opposed to direct coupling as discussed below by causing it to dissociate into two sub-proteins.
Where ion channels are activated directly or an enzyme is activated in the neuron. The G-protein is composed of a complex of three subunits (α, β and γ). The α-subunit contains GTPase activity, where as the other two subunits β and γ remain together forming a complex functioning mainly to support α-subunit. This family of receptors undergo a conformational change as the ligands bind to them. The G-protein is thus exposed decreasing the affinity of the G-protein for guanosine diphosphate (GDP). The now vacant binding site is occupied by guanosine triphosphate which is present in high concentrations in the cytoplasm. The α-subunit dissociates from both the receptor and β-γ complex diffusing into the membrane where it binds to the effector. This procedure is then de-activated by hydrolysis where the α, β, γ trimer are reunited. G-protein coupled receptors are divided into five distinct families (A - E) where groups A - C are present in animals. Family A is the largest of the three and is known as the rhodopsin family. It consists of receptors for most amine neurotransmitters and neuropeptides. Family B is comprised of receptors for peptide hormones and is known as being the secretin/glucagons family. The smallest is family C which consists of the metabotroic glutamate and calcium-sensing receptors.
If G-protein coupled receptors are exposed to their ligand for long periods of time they become less sensitive to it. Therefore dependent protein kinases known as cyclic AMP are activated which in return phosphorylate the receptor.
An example of G-protein coupled receptors is the muscarinic acetylcholine receptor. It has a fast response, occurring within seconds. In this example the G-protein coupled receptor stimulates ionic currents which in return initiate a second messenger cascade. The increase in concentration of second messengers activates other enzymes within the cell.
Whilst the ligands of G-protein coupled receptors typically bind within the transmembrane, other types of receptors such as the ligand-gated ion channels bind externally to the membrane. This family of receptors is the basic, most uncomplicated of the four. They are involved mainly in fast excitatory or inhibitory synaptic neurotransmission that occur within milliseconds. Ligand-gated ion channels are composed of three recognised states which consist of a rested, activated and inactivated state. They are composed of multiple subunits that collectively form an ion channel through the plasma membrane. An example of ligand gated ion channels is the nicotinic ACh receptor of skeletal muscle and related tissues which is also the best known and most studied neurotransmitter. It obtains an oligomeric structure composed of five subunits (α, β, γ, δ). A cluster of these subunits are formed surrounding the ion channel, keeping it closed. This therefore prevents any ions from flowing through the channels. The two α subunits contain acetylcholine binding sites, where once acetylcholine binds the subunits undergo a conformational change resulting in the opening of the aqueous channel. The receptor can only be activated providing both α subunits are occupied. An action potential is then generated leading to the contraction of the muscle as sodium ions diffuse down their concentration gradient and into the cell causing depolarisation.
Kinase-linked receptors consist of single transmembrane helix where large extracellular regions are connected to the intracellular domains containing around 400 – 700 residues. When compared to both G-protein coupled receptors and ligand-gated channels, kinase-linked receptors differ both in structure and function. The binding of a ligand (extracellular) leads to the dimerisation of pairs of receptors due to the two domains being linked via single polypeptide chains, causing autophosphorylation of the tyrosine residues in kinase domains to occur. This autophosphorylation of the receptor as a result acts as a binding site of high affinity for other intracellular proteins leading to tissue response. Examples of these are insulin, the growth factor pathway such as cell division and the cytokine pathway which includes the synthesis as well as release of inflammatory mediators. Even though these hold similar structural properties they however differ in the way they function as the extracellular domain for the insulin receptor has a separate polypeptide which is combined by disulfide bonds to the rest of the molecule. Where as the growth factor receptors have a long single chain consisting of up to a thousand residues.
Nuclear receptors have the slowest response, taking hours even days before any effects start to show. They are situated in the nucleus obtaining a monomeric structure (single polypeptide), which are separated into three functional domains. They consist of receptors for hormones such as steroid and thyroid. In this type of family, the ligands are lilophilic compounds that are adequately lipid soluble to cross the membrane resulting in them binding to intracellular receptors. Consequently gene transcription is regulated as the intracellular proteins function as dimeric molecules. The dimmer molecules bind to hormone-responsive elements of the nuclear DNA and specific genes are either induced or repressed depending on the type of hormone molecule. This hence produces different physiological effects as a result of the protein synthesis patterns altering.
Overall in conclusion the four super families of receptors discussed, consist of very different structural as well as functional properties. They nevertheless are still equally as important. It is crucial to grasp an understanding of these families and their mechanism of as drug receptor interactions are critically significant when making decisions concerning choosing a drug for treatment. This is because when doing so numerous characteristics need to be considered, such as whether a direct or indirect effect is needed to be achieved or the time course of drug action that needs to take place.
