Role and Functions of Second Messengers | Pharmacodynamics

After reading this article you will learn about the role and functions of second messengers.

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, guanylate cyclase or activation of a transport systems or opening of an ion-channel.

These cytoplasmic components which carry forward the stimulus from the receptors are known as second messengers the first messenger being the receptor itself. Examples of second messengers are-cAMP, cGMP, ca²⁺, G-proteins, IP₃, DAG, etc.

The role of cAMP as a second messenger was first revealed by the work of Sutherland in late 1950’s. This discovery demolished the barriers that existed between biochemistry and pharmacology. cAMP is a nucleotide synthesised within the cell from ATP by the action of adenylate cyclase in response to activation of many receptors. It is inactivated by hydrolysis to 5′-AMP, by the action of enzyme phosphodiesterase.

cAMP has varied regulatory effects on cellular functions, for example, energy metabolism, cell division and cell differentiation, ion-transport, ion-channel function, smooth muscle contractility etc. These varied effects are brought about by a common mechanism, namely the activation of various protein kinases by cAMP.

Many different drugs, hormones of neurotransmitters produce their effects by increasing or decreasing the catalytic activity of adenylate cyclase and thus lowering or raising the concentration of cAMP within the cell. The cAMP levels in the cell can also be raised by inhibiting the metabolizing enzyme phosphodiesterase.

Cyclic guanosine monophosphate is another intercellular messenger synthesised by the enzyme guanylate cyclase from GTP. It has been identified in cardiac cells, bronchial smooth muscle cells, and other tissues. For most of the effects produced, cAMP seems to be stimulatory while cGMP seems to be inhibitory in nature.

When the cAMP and cGMP systems are both present in a single cell or tissue, they are linked to receptors through which drugs produce opposite effects. For examples in cardiac tissue cells, β-adrenoceptors increase the frequency and force of contraction by increasing cAMP levels, whereas cholinergic receptors have opposite effect by increasing cGMP levels.

The IP₃ and DAG system is another important intracellular second messenger system, and was identified first by Michell in 1975. Both are degradation products of membrane phospholipids; by an enzyme phospholipase C. IP₃ acts very effectively to release calcium from intracellular stores. This Ca²⁺ is known to regulate the function of various enzymes, contractile proteins and ion- channels.

DAG directly activates protein kinase C and controls phosphorylation of ammo acids of a variety of intracellular proteins. This causes release of hormones from endocrine glands or modulates neuro­transmitter release or modulates smooth muscle contractibility or inflammatory responses or ion-transport or tumour promotion etc. There exist at least six different types of PKC distributed unequally in different cells.

Activation of another enzymes phospholipase A₂ leads to production of arachidonic acid from the membrane phospholipids, which are further broken down to prostaglandins, leukotrienes, thromboxanes etc.

They are well known for their role as local hormones, but it is of interest that arachidonic acid itself and its metabolites have recently been shown to function as intracellular, messengers, controlling potassium channel function in certain neurons.

Calcium ions are of great importance amongst many other intracellular second messengers. Many regulatory actions are mediated by Ca²⁺ bound to its intracellular regulatory protein, calmodulin. Ca²⁺ ions are also involved in release of arachidonic acid from membrane phospholipids by activated phospholipases and so initiate the synthesis of prostaglandins and leukotrienes. Ca²⁺ in synergism with PKC have been shown to activate cellular function like hepatocyte glycogenolysis, insulin release from pancreas. Ca²⁺ also plays an important role in contraction and relaxation of skeletal and smooth muscles of body.

G-Proteins:

G-proteins represent the level of middle management in the cellular organisation and are able to communicate between the receptors and the effector enzymes or ion-channels. They were called G-proteins because of their interaction with the guanine nucleotides, GTP and GDP.

The G proteins are bound to the cytoplasmic surface of the plasma membrane. They are heterotrimeric molecules consisting of 3 subunits α, β and γ (fig 3.10). Their classification as stimulatory or inhibitory is based on the identity of their distinct α subunit.

The β and γ subunits remain associated as β γ complex with the cytoplasmic surface of the membrane when the system is inactive or in resting state, GDP is bound to the α subunit.

Whenever an agonist interacts with the receptor, this facilitates GTP binding to α subunit and promotes dissociation of GDP from its place. Binding of GTP activates the α subunit and α-GTP is then thought to dissociate from β and interact with a membrane bound effector.

The process is terminated when the hydrolysis of GTP to GDP occurs through the GTpase activity of the α-subunit. The resulting α-GDP then dissociates from the effector, and reunites with β γ completing the response cycle. Attachment of the subunit to an effector molecule actually increases its GTpase activity, the magnitude of this increase varies for different types of effector.

Mechanisms of this type in general result in amplification because a single agonist receptor complex can activate several G-protein molecules in turn, and each of these can remain associated with the effector enzyme for long enough to produce many molecules of product.

The product is often a second messenger, and further amplification occurs before the final cellular response is produced. It is the biological adaptation of an organism for judicious use of its transmitter substances.

G-proteins are not all identical, the α-subunit in particular shows variability. It is believed that there are three main varieties of G-protein viz. G_s, G_i and G_q. G_s and Gi produce respectively stimulation and inhibition of the effector system (fig. 3.11). It is not unusual for several receptors in an individual cell to activate a single G protein and a single receptor regulating more than one G-proteins.

It is now known that the membrane enzymes like adenylate cyclase, phospholipase C, phospholipase A, as well as a variety of ion-channels are controlled through this intra-membrane managers, G-proteins metabotropic receptor is the term used for G-protein coupled receptors which operate through intracellular second messengers e.g., mAChR, adrenoceptors and neuropeptide receptors