Receptor Subtypes

RECEPTOR SUBTYPES

The delineation of multiple types and subtypes of receptors for signal molecules has played an important role in the development of a number of targeted and more selective drugs. Even at an early stage of evolution of receptor pharmacology, it was observed that actions of acetylcholine could be grouped into ‘muscarinic’ and ‘nicotinic’ depending upon whether they were mimicked by the then known alkaloids muscarine or nicotine. Accordingly, they were said to be mediated by two types of cholinergic receptors, viz. muscarinic or nicotinic (N); a concept strengthened by the finding that muscarinic actions were blocked by atropine, while nicotinic actions were blocked by curare. In a landmark study, Ahlquist (1948) divided adrenergic receptors into ‘α’ and ‘β’ on the basis of two distinct rank order of potencies of adrenergic agonists. These receptors have now been further subdivided (M1, M2 ….M5), (NM, NN) (α1, α2) (β1, β2, β3). Multiple subtypes of receptors for practically all transmitters, autacoids, hormones, etc. are now known and have paved the way for introduction of numerous clinically superior drugs. In many cases, receptor classification has provided sound explanation for differences observed in the actions of closely related drugs.

The following criteria have been utilized in classifying receptors:

 a. Pharmacological Criteria

Classification is based on relative potencies of selective agonists and antagonists. This is the classical and oldest approach with direct clinical bearing; was used in delineating M and N cholinergic, α and β adrenergic, H1 and H2 histaminergic receptors, etc.

 b. Tissue Distribution

The relative organ/tissue distribution is the basis for designating the subtype, e.g. the cardiac β adrenergic receptors as β1, while bronchial as β2. This division was confirmed by selective agonists and antagonists as well as by molecular cloning.

 c. Ligand Binding

Measurement of specific binding of high affinity radio-labelled ligand to cellular fragments (usually membranes) in vitro, and its displacement by various selective agonists/antagonists is used to delineate receptor subtypes. Multiple 5HT receptors were distinguished by this approach. Autoradiography has helped in mapping distribution of receptor subtypes in the brain and other organs.

d. Transducer Pathway

Receptor subtypes may be distinguished by the mechanism through which their activation is linked to the response, e.g. M cholinergic receptor acts through Gproteins, while N cholinergic receptor gates influx of Na+ ions; α adrenergic receptor acts via IP3DAG pathway and by decreasing cAMP, while β adrenergic receptor increases cAMP; GABAA receptor is a ligand gated Cl– channel, while GABAB receptor increases K+ conductance through a Gprotein.

e. Molecular cloning

The receptor protein is cloned and its detailed amino acid sequence as well as three dimentional structure is worked out. Subtypes are designated on the basis of sequence homology. This approach has in the recent years resulted in a flood of receptor subtypes and several isoforms (which do not differ in ligand selectivity) of each subtype. The functional significance of many of these subtypes/ isoforms is dubious. Even receptors without known ligands (orphan receptors) have been described.

Application of so many approaches has thrown up several detailed, confusing and often conflicting classifications of receptors. However, a consensus receptor classification is now decided on a continuing basis by an expert group of the International Union of Pharmacological Sciences (IUPHAR).

f. Silent Receptors

These are sites which bind specific drugs but no pharmacological response is elicited. They are better called drug acceptors or sites of loss, e.g. plasma proteins which have binding sites for many drugs. To avoid confusion, the term receptor should be restricted to those regulatory binding sites which are capable of generating a response.