INTRODUCTION:

In 1901, John Langley challenged the dominant hypothesis that drugs act at nerve endings via demonstrating that nicotine act as at sympathetic ganglia yet after the degeneration of the severed preganglionic nerve endings [1]. In 1905 he introduced the concept of a accessible substance on the surface of skeletal muscle that mediated the action of a drug. It also postulated that these accessible substances were different in different species [2]. About the same time, Ehrlich was trying to understand the basis of selectivity of agllents [3]. He was the basis of a preferential distribution of lead and dyes in different body tissues. But, he afterward modified the theory in order to explain immune reactions and the selectivity of the immune response [4].

These are the macromolecules it made up of proteins materials which is located in surface of the cell within the cell membrane cytosol, transmembrane or nucleus. A receptor is protein in nature that receives chemical signals from outside a cell [5]. When a chemical signals binds to a receptor they cause cellular/tissue response, e.g. a change in the electrical activity of a cell. In this sense, a receptor is a protein-molecule that recognizes and responds to endogenous chemical signals, e.g. A ligands acetylcholine affinity binds to an acetylcholine receptor and they recognizes and responds to its endogenous ligand, acetylcholine. However, now and again produced of pharmacology action, the term is also used to include other proteins that are drug targets, such as enzymes, transporters and ion channels [6].

Theories of drug-receptor interaction:

Drug-receptor interaction theory has been proposed as followings:

I Occupation Theory

II Rate Theory

III Induced Theory

IV macromolecular Theory

V Activation-aggregation Theory.

Types of receptors:

The structures of receptors are especially varied and they can be generally classified by following categories:

Ligand gated ion channel (Ionotropic receptors):

Ligand-gated ion channels (LICs), are also usually referred as an ionotropic receptors, are a group of transmembrane ion channel proteins which open to allow ions such as Na+, K+, Ca2+, and Cl− to go through the membrane in response to the binding of a chemical messenger (i.e. a ligand) such as a neurotransmitter [7].

These proteins are usually consisting of at least two different domains: a transmembrane domain which includes the ion pore and an extracellular domain which includes the ligand binding location (an allosteric binding site). This modularly has enabled a part and overcome advance to finding the structure of the proteins. The function of such a receptors located at synapses is to altered the chemical signal of presynaptically released neurotransmitter directly and very rapidly into a postsynaptic electrical signals.

Many ligand gated ion channels are also modulated by allosteric ligands via channel blockers, ions, or the membrane potential. Ligand gated Ion channels are classified into three Channels which lack evolutionary correlation: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels. The receptors are subdivided with respect to the type of ion that they behavior (anionic or cationic) and further into defined by the endogenous ligand. They are usually pentameric with 2α,β,γ,δ subunit containing 4 transmembrane helices constituting the transmembrane domain [8].

G protein-coupled receptors (Metabotropic):

The 2012 Nobel Prize in chemistry was awarded to Brian Kobilka and Robert Lefkowitz for their work that was “crucial for understanding how G-protein coupled receptor function”. There have been at least seven other Nobel Prizes awarded for some aspect of G protein–mediated signaling As of 2012, two of the top ten global best-selling drugs act by targeting G protein–coupled receptors [9]. G protein coupled receptors (GPCRs) which are also known as seven-transmembrane domain receptors (7TM), hepta-helical receptors, serpentine receptors, and G-protein-linked receptors (GPLR).

It is constitute a great protein family of receptors to detect molecule outside the cell and active internal signal transduction pathway and produce a cellular response. Coupling with G protein. It is called as seven transmembrane receptors, because they pass through the cell membrane seven times [10].

GPCR are found in eukaryotes including yeast choanoflagellates. and animals the ligands that bind and activate these receptors including light sensitive compounds, hormones, and neurotransmitter. GPCR are involved in many disease and are also the target of approximately 40% of all modern medicinal drugs [11].

There are two principal signal transduction pathways involving the G protein–coupled receptors:

· The cAMP signal pathway and

· The phosphatidylinositol signal pathway [12].

When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13) [13].

(a) GPCRs Signaling:

If a receptor in an active state encounters a G protein, it may activate it. Some ev/idence suggests that receptors and G proteins are actually pre-coupled [14]. For example, binding of G proteins to receptors affects the receptor's affinity for ligands. Activated G proteins are bound to GTP. Further signal transduction depends on the type of G protein. The enzyme adenylatecyclase is an example of a cellular protein that can be regulated by a G protein, in this case the G protein Gs.

Adenylatecyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylatecyclase ends when the G protein returns to the GDP-bound state. Adenylatecyclases (of which 9 membrane-bound and one cytosolic forms are known in humans) may also be activated or inhibited in other ways (e.g., Ca2+/Calmodulin binding), which can modify the activity of these enzymes in an additive or synergistic fashion along with the G proteins.

The signal pathway activated through a GPCR are limited by the primary sequence and tertiary structure of GPCR itself but ultimately determined by particular conformation stabilized by a particular ligand as well as the availability of transducer molecules. Currently GPCRs are considered to utilize two primary type of transducer: G-proteins and β-arrestins [15].

(b) cAMP signal pathway:

Cyclic adenosine 3′,5′-monophosphate (cAMP) was the first second messenger to be identified and plays fundamental roles in cellular responses to many hormones and neurotransmitters. The cAMP signal transduction is contains 5 major characters:

· Stimulative hormone receptor (Rs) or inhibitory hormones receptors (Ri)

· Stimulative regulative G protein (Gs) or inhibitory regulative G protein (Gi)

· Adenylyl cyclase (AC)

· Protein kinase A (PKA)

Stimulative hormone receptor (Rs) is a receptor which can binds with stimulative signal molecules and while inhibitory hormone receptor (Ri) is a receptor which can binds with inhibitory signal molecules. Stimulative regulative G-protein is a G-protein linked to stimulative hormone receptor (Rs), and it’s α subunit ahead activation could stimulate the activity of an enzyme or other intracellular metabolism. Not at all inhibitory regulative G-protein is linked to an inhibitory hormone receptor and it’s α subunit ahead activation could inhibit the activity of an enzyme or other intracellular metabolism.

Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes ATP to form cAMP with the help of cofactor Mg2+ or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator of protein kinase A. The Protein kinase A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylation with specific enzymes in the metabolic pathway. It can also regulate specific gene expression, cellular secretion, and membrane permeability.

When cAMP binds to the regulatory subunits, their conformation is changed their causing the dissociation of the regulatory subunits, which activates protein kinase A and allows further biological effects or activities. These signals then can be terminated by cAMPphosphodiesterase, which is an enzyme that degrades cAMP to 5'-AMP and inactivates protein kinase A [16].

(c) Phosphatidylinositol signal pathway:

In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G protein receptors (Gq) on the cell surface and activate phospholipase C. which is located on the plasma membrane. The lipase hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers:

· Inositol 1,4,5-trisphosphate (IP3) and

· Diacylglycerol (DAG).

IP3 binds with the IP3 receptor in the membrane of the smooth endoplasmic reticulum and mitochondria and due to open Ca2+ channels. DAG through activate the protein kinase C (PKC), which phosphorylates or many other proteins, changed their catalytic activities and leading to cellular responses. The effects of Ca2+ are also significant it cooperates with DAG in activating PKC and they can activate the CaM(calcium-modulated protein calmodulin) kinase pathway. In which CaM binds Ca++ undergoes change in conformation and activates the CaM kinase II. Which has single ability to increases its binding affinity to CaM by autophosphorylation. The kinase then phosphorylates target enzymes, regulating their activities.

(d) Tyrosine and histidine kinase:

Receptor tyrosine kinase(RTKs) are transmembrane protein with an intracellular kinase domain sites and extracellular domain sites that’s bind ligands. eg include growth factor receptors such as the insulin receptor. [17] To perform signal transduction, RTKs need to form dimers in the plasma membrane [18]. The interaction between the cytoplasmic domains stimulates the auto phosphorylation of tyrosine residues within the intracellular kinase domains of the RTKs, their causing conformational changes.

Subsequent to this the receptors' kinase domains are activated, initiating phosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as cell differentiation and metabolism [19]. As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK into the cell. In this case, the G proteins are members of the RAS and RAF families, referred to as small G proteins. They act as molecular switches usually tethered to membranes by isoprenyl groups linked to their carboxyl ends. Activated RTKs in turn activate small G proteins that activate guanine nucleotide exchange factors.

Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor's initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors that exist in a constitutively activate state such as mutated genes may act as oncogenes [20]. It specific protein kinases are structurally dissimilar from other protein kinases and are found in prokaryotes of cells, fungi, and plants as part of a two-component signal transduction mechanism a phosphate group from ATP is first added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a different protein or the kinase itself, thus activating the aspartate residue [21].

(e) Second Messengers:

First messenger are the signaling molecules (NT/hormones) that get to the cell from the extracellular fluids and binds to their specific receptors. Second messengers are the substances that go into the cytoplasm and act within the cell to trigger a response. In case second messenger serve as chemical relay from the plasma membrane to the cytoplasm thus carrying out intracellular signal transduction [22].

(I) IP3- DAG:

Inositol 1,4,5 triphosphate are also known as IP3 together with diacylglycerol (DAG), is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane IP3 is soluble and diffuses through the cell. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) a phospholipid that is located in the plasma membrane, by phospholipase C (PLC).

(II) Signal mechanism of IP3:

Increases in the intracellular Ca2+ concentrations are often a result of IP3 activation. When a ligand binds to a G protein-coupled receptor (GPCR) that is coupled to a Gqheterotrimeric G protein, the α-subunit of Gq can bind to and induce activity in the PLC isoenzyme PLC-β, which results in the cleavage of PIP2 into IP3 and DAG [23]. If a receptor tyrosine kinase (RTK) is involved in activating the pathway, the isozyme PLC-γ has tyrosine residues that can become phosphorylated upon activation of an RTK, and this will activate PLC-γ and allow it to cleave PIP2 into DAG and IP3.

This occurs in cells that are capable of responding to growth factors such as insulin, because the growth factors are the ligands responsible for activating the RTK. IP3 (also abbreviated Ins3P) is a soluble molecule and is capable of diffusing through the cytoplasm to the ER, or the sarcoplasmic reticulum (SR) in the case of muscle cells, once it has been produced by the action of PLC. Once at the ER, IP3 is able to bind to the Ins3P receptor (Ins3PR) on a ligand-gated Ca2+ channel that is found on the surface of the ER. The binding of IP3 (the ligand in this case) to InsP3R triggers the opening of the Ca2+ channel, and thus release of Ca2+ into the cytoplasm [24].

Receptor Tyrosine Kinase (Enzyme-linked receptor):

Tyrosine phosphorylation is a highly regulated post-translational modification that is essential for inter- and intracellular communication in metazoans. The enzymes that catalyze phosphoryl transfer to tyrosine residues in protein substrates, using ATP as a phosphate donor, are the protein tyrosine kinases, of which there are 58 receptor types (RTKs) and 32 non-receptor types in the human genome [25]. The RTK family includes, among others, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptors, fibroblast growth factor receptors (FGFRs), vascular endothelial growth factor receptors, Met (hepatocyte growth factor/scatter factor [HGF/SF] receptor), Ephs (ephrin receptors), and the insulin receptor.

RTKs are essential components of cellular signaling pathways that are active during embryonic development and adult homeostasis. Because of their roles as growth factor receptors, many RTKs have been implicated in the onset or progression of various cancers, either through receptor gain-of-function mutations or through receptor/ligand overexpression. [26] RTKs are single-pass, type I receptors resident in the plasma membrane. Generally, RTKs are activated through ligand-induced oligomerization, typically dimerization, which juxtaposes the cytoplasmic tyrosine kinase domains [27]. These are 2 major pathway of the receptor tyrosine kinase (RTKs):-

· MAPK/ERK pathway

· RAS/RAF/MEK/ERK pathway

· JAK/STAT signaling pathway.

(a) MAPK/ERK pathway:

The MAPK/ERK pathway are also known as the Ras-Raf-MEK-ERK pathway this is a chain of proteins in the cell that thecommunicates a signal to a receptor on the surface of the cell membrane to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division.

The pathway includes many proteins, including MAPK mitogen-activated protein kinases, initially called ERK, extracellular signal-regulated kinases which communicate by adding phosphate groups to a neighboring protein, which acts such as an on or off switch. When one of the proteins in the pathway is mutated, it can develop into stuck in the on or off position, which is a essential step in the development of many cancers. Components of the MAPK/ERK pathway were discovered when they were found in cancer cells. Drugs that reverse the on or off switch are being investigated as cancer treatments [28].

(b) RAS/RAF/MEK/ERK pathway:

The Ras/Raf/MEK/ERK cascade couples signals beginning cell surface receptors to transcription factors, which is regulate gene expression. Still this cascade also regulates the activity of many proteins involved in apoptosis. This pathway is often activated in certain tumors by chromosomal translocations like BCR-ABL [29].A increase in the complexity of this pathway, as there are multiple members of the kinase, transcription factor, apoptotic regulator and caspase executioner families, which can be activated or inactivated by protein phosphorylation. At also, this pathway can induce the transcription of certain genes.

Raf, either from downstream MEK and ERK, or independently of MEK and ERK it can induce the phosphorylation of proteins, which control apoptosis. In additional signal transduction pathways interact with the Raf/MEK/ERK pathway to positively or negatively regulate its activity. The Raf/MEK/ERK pathway also influences chemotherapeutic drug resistance as ectopic activation of Raf induces resistance to doxorubicin and paclitaxel in breast cancer cells [30]. For all the more than reasons, the Raf/MEK/ERK pathway is an important pathway to target for therapeutic interference. Inhibitors of Ras, Raf, and MEK and some downstream targets have been developed and many are at present in clinical trials [31].

(c) JAK/STAT signaling pathway:

The Janus kinase or signal transducers and activators of transcription (JAK/STAT) pathway is one of the handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide display of cytokines and growth factors. JAK activation stimulates cell proliferation, differentiation, cell migration and apoptosis. These cellular events are critical to hematopoiesis, immune development, mammary gland development and lactation, adipogenesis, sexually dimorphic growth and other processes.

Predictably, mutations that reduce JAK/STAT pathway activity affect these processes [32]. Mechanistically, JAK/STAT signaling is relatively simple with only a few major components [33]. As described above, a variety of ligands and their receptors stimulate the JAK/ST AT pathway. Intracellular activation occurs when ligand binding induces the multimerization of receptor subunits. Signal propagation through either homodimers or heteromultimers, the cytoplasmic domains of two receptor subunits must be associated with JAK tyrosine kinases. The activated JAKs subsequently phosphorylate additional targets, including both the receptors and the major substrates STATs.

STATs are latent transcription factors that reside in the cytoplasm until activated. in the nucleus, dimerized STATs bind specific regulatory sequences to activate or repress transcription of target genes. Thus the JAK/STAT cascade provides a direct mechanism to translate an extracellular signal into a transcriptional response. In addition to the principal components of the pathway, other effector proteins have been identified that contribute to at least a subset of JAK/STAT signaling events [34].

Nuclear Receptor:

The molecular mechanisms of action and the role of nuclear transcription factors in their functional environment, the cell nucleus, have been intensively studied and partially revealed. This holds true in particular for steroid and thyroid hormone receptors, a major class of the super family of nuclear receptors, representing ligand activated transcription factors, involved in the regulation of metabolic, growth, developmental and immune processes [35].

In the ligand unbound, non-activated state, these receptors are components of a macromolecular complex with heat shock and other proteins [36].Activated by extracellular or intracellular regulatory molecules, involved in cell growth, differentiation survival and apoptosis [37-39]. Until recently, research on how the nuclear receptors and the other transcription factors exert their physiological functions was centered mainly on their action within the nuclear environment and their interaction with nuclear genes [40-41].

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Received on 12.06.2017 Modified on 16.09.2017

Res. J. Pharmacology and Pharmacodynamics.2017; 9(4): 223-229.

DOI: 10.5958/2321-5836.2017.00040.4