Receptors
Receptor theories
1. Occupation theories
A.J.Clark propounded the occupation theory which assumes that the extent to which a tissue is dependent on the proportion of its receptor population that has been occupied by a drug and maximal response is reached when all the receptors are occupied. He presumed that each occupied receptor delivered a constant unit of response and that this individual occupancy stimuli was summated in mathematical fashion to give a linearly proportional response. But this theory was not applicable in all situations. In the case of partial agonists a maximal response could not be exhibited even though all the receptors were occupied.
E.J.Ariens, divided the biological response into two separate parameters namely affinity and intrinsic activity. Affinity described the binding of the drug to the receptor and was assumed to be governed by mass action. Intrinsic activity was related to the ability of the drug to induce an effect after binding. The assumptions are the same as those for Clarke’s theory. However, the notion of partial agonism can be accounted for by assuming a lower intrinsic activity for a partial agonist than for a full agonist. Again, a discrepancy between EC50 and KD values and the observations of spare receptors could not be explained.
R.P.Stephenson, assumed that the drug receptor complex provides a stimulus to the tissues and that the stimulus is directly proportional to the fraction of receptors occupied. The response is then related to the stimulus by an unspecified function. The proportionality factor between the fractional occupancy of the receptor population was defined as the efficacy. The efficacy of a drug refers to the action of the drug to produce a response in a given tissue. An additional parameter, intrinsic activity was defined to describe the stimulant activity of the drug itself independent of the tissue. The problem with Stephenson’s model is that the exact link between effect and occupancy remains unclear.
2. Rate theory
Rate theory was developed by W.D.M. Paton and postulates that the biological response is proportional to the rate at which the drug combines with the receptor – that is, each association of the drug with receptor results in a quantum of excitation. This implies that an agonist must dissociate rapidly from the receptor to enable other successful associations and subsequent generation of quantum of excitation.
On the other hand, an antagonist is assumed to dissociate slowly to prevent the generation of other quanta of excitation. Thus, dissociation rate constant was considered to be the factor, which determined whether a ligand was an agonist, antagonist or partial agonist. The experimental analysis of drug dissociation rates did not support this model.
3. Allosteric theories
Two allosteric models originally developed to describe enzyme regulation have been proposed. The idea of the allosteric theory is that receptors can exist in a variety of discrete conformational states differing in their ability of that state to produce a response.
Ligands then interact with the receptor in such a way so as to control the conformational state. These models define precisely the relationship between binding and effect.
Receptors sub serve two essential function viz., recognition of the specific ligand molecule and transduction of signal with a response. Accordingly, the receptor has a ligand binding domain (spatially and energetically suitable for binding the specific ligand) and effector domain, which undergoes a functional conformational change.
Functions of receptors
- To propagate regulatory signals from outside to within the effector cell when the molecular species carrying the signal cannot itself penetrate the cell membrane
- To amplify the signal
- To integrate various extracellular and intracellular regulatory signals
- To adapt to short term and long term changes with regulatory milieu and maintain homeostasis.
Types of receptors
- Type I – Channel linked receptors (ligand-gated ion channels or inotropic receptor) – These are also known as ionotropic receptors. These are membrane receptors that are coupled directly to ion channels and are the receptors on which fast neurotransmitters act. Examples include nicotinic acetylcholine receptors and glutamate receptors.
- Type II – G-Protein coupled receptors (metabotropic receptors) – These are also known as metabotropic receptors or 7-transmembrane spanning receptors. They are membrane receptors that are coupled to intracellular effector systems via a G-protein. This class includes receptors for many hormones and slow transmitters. Examples include muscarinic acetylcholine receptors and adrenergic receptors.
- Type III – Kinase-linked receptors – These are membrane receptors that incorporate an intracellular protein kinase domain within their structure. They include receptors for insulin, various cytokines and growth factors. Closely related are receptors linked to guanylate cyclase such as the atrial natriuretic factor receptor.
- Type IV – Receptors that regulate gene transcription (nuclear receptors) – These are also known as nuclear receptors, though some are actually located in the cytosol rather than the nuclear compartment. They include receptors for steroid hormones and thyroid hormone.
Second messenger systems
Many hormones, neurotransmitters, autacoids and drugs act on specific membrane receptors, the immediate consequence of which is activation of a cytoplasmic component of the receptor, which may be an enzyme such as adenylate cyclase, guanyl cyclase or activation of a transport system or opening of an ion channel.
These cytoplasmic components which carry forward the stimulus from the receptors are known as second messengers. The receptor itself is the first messenger. Examples of second messengers are cAMP, cGMP, Ca2+, G-Proteins, IP3, DAG etc.
cAMP serves as second messenger for adenosine, opioid, VIP, α2 and β adrenoceptors and H2 receptors.
cGMP serves as second messenger for angiotensin receptor.
IP3 and DAG serve as second messengers for α1 adrenoceptors, H1 receptors and cholecystokinin.
cAMP has varied regulatory effects on cellular functions, for example, energy metabolism, cell division and cell differentiation, ion-transport, ion-channel funtion, smooth muscle contractility etc.
cGMP has ben identified in cardiac cells, bronchial smooth muscle cells and other tissues. For most effects produced cAMP seems to be stimulatory while cGMP seems to be inhibitory in nature. When the cAMP and cGMP systems are bothe present in a single cell or tissue, they are linked to receptors through which drugs produce opposite effects. IP3 and DAG are degradation products of membrane phospholipid by the enzyme phospholipase C.