Receptor Multiplicity





Receptor Multiplicity By Christian George


Over the past three decades the diversity and selectivity of ligands has increased and it has become clear and evident that multiple subtypes of receptors exist. That is subtypes within many previously defined classes of receptors. Due to the advances in scientific research especially over the past decade with molecular cloning, there has been a revelation in the presence of several closely related subtypes of receptors where only a single species was thought to exist, and some receptor subtypes have been shown to be differentially expressed during development, differentially regulate physiological systems, regulate transmitter release, be involved in permanent changes in the brain via integration. Knowledge of receptor subtypes is of interest to the researcher, at present many studies are being carried out into the investigation of new receptors and the mechanisms of known receptors. Manipulation of the receptors has now been achieved facilitating the search for new receptors. There is a huge diversity and receptor multiplicity involving subtypes and a few examples are going to be discussed in this essay involving some history and identification of subtypes, various imaging of subtypes, and some of the more detailed roles that they play in our physiological systems with pharmacological experimental evidence to support this.

The term “receptor multiplicity” was mentioned above from carrying out research there is no general definition of “receptor multiplicity”, however there are examples which display “receptor multiplicity”. The Opioid receptors have been subtyped, and there is evidence for the existence of  receptor multiplicity. The evidence is supported by the fact that high affinity 1 receptors not only bind morphine but enkephalins as well, in addition to 2 receptors that preferentially bind morphine. This demonstrates that receptor subtypes in the  type opioids exist defining receptor mutiplicity, it means a class of receptors say adrenergic has subtypes within that class. These adrenergic subtypes allow endogenous noradrenaline to bind and activate the receptor resulting in a biological change, but specific ligands can also activate a selective subtype in that class of receptors without affecting the other subtypes for example salbutamol is an agonist of the 2 adrenoceptor only and produces bronchodilation, it is used in the treatment of asthma and produces little side affects due to it’s selectivity.

Different subtypes of the same receptor class can also mediate different biological responses at different locations in the body, the nicotinic cholinergic receptor for example, when antagonised in the ganglia to control blood pressure does not affect the nAChR in skeletal muscle paralysing it. Other agents such as tubocurarine has the ability to antagonize the action of acetylcholine at the neuromuscular junction and is confined to this location. These subtypes of receptor are analogous to tissue specific isozymes of an enzyme.

There are two main mechanisms of receptor G –protein coupled receptors and ligand gated ion channels. These two types can occur in the same family for example the serotonin receptor class are all G protein coupled receptors apart from 5HT3 which is a ligand gated ion channel. The differences in these two type will be explained later on(Figs. 1 and 2). The mechanisms of action of some receptor subtypes may be very similar, differing only slightly in kinetics or regulatory activity, but other subtypes the G protein coupled receptors display fundamental differences in their biochemical and cellular regulatory activities. For example 1 and 2 adrenergic and M1 and M2 muscarinic cholinergic subtypes. All four subtypes regulate G proteins, the 1 Figure 3adrenergic and the M1 and M3 muscarinic receptors initiate Ca2+ signalling via Gq, in contrast the 2 adrenergic and M2 and M4 muscarinic receptors regulate other signalling pathways via GI and another GTP binding protein, G0 (Fig. 2). Expression of such different receptor subtypes allows a single agonist to evoke unique responses in specific cells or tissues.


Figure 1. G-Protein coupled receptor Figure 2. Ligated ion channel receptor
In the recent decade advances in scientific research have accomplished the art of cloning. Using these techniques in combination with radioligand binding and autoradiography, novel receptors have been identified and implemented using these molecular biological techniques. If a tissue or cell expresses more than a single subtype of receptor or when only insufficiently selective drugs are available identification of the specific signal that is generated by an individual receptor requires more direct