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G protein-coupled receptors majorly include biochemical pathways that facilitate scientist to contribute lots of researches related to diseases such as; psychiatric illnesses-multiple personality,bipolar,depression,anxiety and final example of describing relationship is schizophrenia[1].Recently,clinical examinations of GPCR(G protein-coupled receptors) are exponentially rising up in genetics and pharmacology.As a brief explanation of how GPCR are related to schizophrenia is to provide by neurotransmitters and signaling pathways in brain.An alteration of neurotransmitters and neuropeptide in GPCR involved in frontal cortex, hippocampus, hypothalamus and brainstem that affect cognitive skills and motor developments (Lisa A. Catapona&Husseini K.Manji, 2009).Schizophrenia has immensely impact on human’s social and psychological life.Improvement of a drug which is cohorently related to psychiatric diseases has initiated in 1950 and 1960 by scientists,after all researchers about psychiatry have detected relationships with molecular biology,genetics and pharmocology that define as renewed studies are followed by.Thanks to GPCR,several drugs may affect human brain system that highly responsible of psychiatric diseases then diminish failures of psychiatric diseases in general schizophrenia,this paper aims to explain what GPCR implements to clarify what type of receptors tightly include. Furthermore, ,bipolar disorder ,manic-depressive disorders, dysthymia are referred mood disorders that mainly physiological disorders,nowadays more than 450 millions in 8 billion people suffer from mental illnesses,however schizophrenia can not be categorized in the statement of mood disorders,in the abstract mood disorders are deeply involved. [1],[2]
According to The World Health Organization,mental disorders are assessed that disabling brain cells and relating cells cause psychiatric illnesses,evaluations have demonstated more than 40% people in USA related to it.Also diversity of psychomotor activity procures many subjects that are depressed mood, suicidal ideation, anhedonia-the disability of feeling pleasure- (Lisa A. Catapona&Husseini K.Manji, 2009).Developments of medical drugs such as; antidepressant curing psychiatric illnesses that affect serotonin inhibitors, attaining hormones; norepinephrine, dopamine and serotonin. [3]
Schizophrenia is a disorder affecting nervous system of a human during the lifetime,occures roundly 1% of human population that results in same percent both woman and man (Lisa A. Catapona&Husseini K.Manji, 2009). As reported in studies about how criteria affects the probability of schizophrenia is related to genetics that human who already has relationship between family relevants possibly more correlates than human in normal population.Symptoms of schizophrenia diagnosed by psychiatrists using some tests as symptoms are readily recognized,In the event; delusions, hallucination and avolition have impact on patients suffering from schizophrenia.Now that,newly found drugs decreasing the effect of schizophrenia assume positive subject about drugs which discover through GPCR.
Dopamine Receptors
Dopamine is major hormone what exactly cause schizophrenia explaining that dopamine is correlated to motor activity,balancing the pleasure level of human,motivation of human.If all these great matters disturbed, schizophrenia,manic depressive disorder and depression readily make human brain’s system exist less effective. [4]The dopamine hypothesis of schizophrenia clarified that in researches of psychiatry,this hypothesis provided lots of subject which is in schizophrenia and other disorders. [5]The Dopamine Hypothesis 1 is explained there,also version two and three occur in drugs found for schizophrenia that inevitable ideas have discovered as treatments of diseases have been insufficient.Moreover, antipsychotic medications are accessed for treating schizophrenia.
Dopamine D2 Receptors are inhibited by variation of hyperactivity of limbic dopaminergic transmission that facilitates motor activity,signaling pathways,cause dopamine to release in brain which is exactly similar symptoms of schizophrenia.Numerous researches are indicated that alteration of dopamine receptors-D2 receptors procure beginning of psychiatric disorders-schizophrenia.According to some reports,D2 receptors can not be distinguished the treatments of all patients who suffer from schizophrenia,almost 70% replents of D2 receptors enable patients to be treat by antipsychotic medications (Lisa A. Catapona&Husseini K.Manji, 2009). [7]
Dopamine D3 Receptors
The D3 receptor polymorphism have been adjusted by lots of studies about schizophrenia that are Ser9Gly which is extensively most known polymorphism recognized by schizophrenia treatments.However all examination of D3 receptor polymorphism- Ser9Gly has not been correlated to responses which enable scientist to ascertain of repling drug cure.[9] Many D3 receptors have been encountered similar results that could not be distinguish any tie between D3 receptors and schizophrenia. [10] [13],[14]
Polymorphisms of Dopamine D2 Receptors
Widespreadly,Dopamine D2 receptors have several polymorphisms that focus on Ser311Cys polymorphism, 141C Ins/Del polymorphism which is located in D2 receptor’s promoter region. [6]In addition to necessary polymorphisms that generally used for recent polymorphisms of schizophrenia, C957T,His313 and the Taq1A polymorphisms are affilitated.Plenty of analysis spanning that relate to major D2 receptors has identified for schizophrenia’s treatment. [8], [11], [12]
Serotonergic Receptors
G protein-coupled receptors has intercorporated to serotonergic receptors that enable debate about how serotonergic receptors are effectively impact on schizophrenia,several medications has applied patients suffering from schizophrenia in order to obtain any responses of how schizophrenia may be diminished through drugs applying. 5HT1A and 5HT2A receptors that can be prioritized in GPCR’ serotonergic receptors. . [15] Moreover,some studies are inferred that 5HT1A operates with dopamine antagonists (Lisa A. Catapona&Husseini K.Manji, 2009).
McCune-Albright Syndrome
McCune-Albright Syndrome is a very scarce genetic disorder that affects only a small proportion of the population. It mainly targets skin, endocrine system and bones. It is also associated with fibrous dysplasia, accompanied by two additional symptoms; defects in skin pigmentation and deficiencies in the regulation of some hormonal glands which later disturbs the growth rate, sexual development and some certain metabolic activities. Fibrous Dysplasia (FD), is a condition resulting from the occurrence of aberrant scar-like fibrous tissue in the bones in any area through the body.[1] The occurrence of fibrous lesions weakens the bones and make them prone to fractures and also it may cause chronic pain.[1] The underlying reason of MAS is a random genetic mutation that occurs in the GNAS1 gene and its reason is still unknown.[2] However, it’s known that MAS is not a genetically inherited mutation indicating that it is a post-zygotic somatic mutation.[2] Even though this syndrome has a wide range of symptoms, some of them may vary from individual to individual and in different scales of severity, since MAS is a syndrome that shows a mosaic genetic pattern.
To be more specific, FD/MSA Syndrome is resulted from a mutation in the GNAS gene which actually codes for the cAMP pathway-associated G-protein, GSα, that occurs in the early embryonic stages of the somatic cells.[3] Therefore, it is not inherited. On the other hand, it does not necessarily mean that the whole set of an affected individual’s GNAS1 gene products are mutated, rather it displays a “mosaic pattern” meaning that the affected individuals encounter both normal and abnormal copies of the gene. [2] Although it is not known what triggers this mutation yet, studies have shown that it occurs sporadically in a population.[3] Additionally, the severity of the syndrome is dependent on the ratio of normal cells to mutant ones.[3] Due to GSα’s biological function, as ubiquitin signaling molecule, even a slight change in its property may eventually cause alterations in the related tissues; bones, skin, endocrinal glands, digestive system and so on. The GNAS1 gene is located on the chromosome “20q13.2” and it normally codes for the G-protein.[2] In MAS, mutations in the Arg201Cys or Arg201His residues result in overproduction of cAMP due to continuous activation of the GSα. [4] Eventually, the excessive amounts of cAMP derives the formation of the symptoms as the outcome. [4] Furthermore, the rate of those symptoms can be distinctive upon individuals by either displaying the major ones or may not show any symptom at all. As mentioned before, polyostotic fibrous dysplasia is one of the major symptoms directly associated with MAS. It generally affects more than one skeletal sites through the body while generally showing a unilateral pattern.[3] Additionally, FD may cause neurological dysfunctions that result in the loss of hearing and vision due to the disruption of of optic and auditory nerves. [2] There are also some skin-related symptoms like “café-au lait” spots, which are resulted from a deficiency in pigmentation. Those spots are abnormally expressed and restricted on one side, like it is divided by a midline, of the body and the accumulation of them my increase with ageing.[5] The last major class of symptoms is endocrinal glands. In a healthy individual, endocrine system is responsible from the regulation of growth, sexual development and some metabolic activities. MAS usually causes an early puberty (gonadotropin independent precocious puberty), which yields in the development of sexual characteristics at very young ages. [2] Studies have confirmed that the females have 50% more tendency for precocious puberty. [2]
The diagnosis may be detected at birth depending on the severity of the visible abnormal symptoms like “café-au lait” spots. On the contrary, in most of the cases the diagnosis is not attained until the precocious puberty occurs at the late phases of infancy. Diagnosis can be performed based on physical symptoms or by the use of clinical tests like x-ray studies or blood tests.[2] The treatment procedure is individualized and shaped by the symptoms of the patient. The treatment procedure usually consists of the combination of therapeutics, psychological support, the efforts of dermatologists, orthopedists and endocrinologists.[2]
GPCR Drug Discovery
As mentioned before, GPCRs are signal transmitters and they are located in the plasma membrane of the cell. Their ability to interact with different signaling elements in a broad range including proteins, peptides, hormones, neurotransmitters, lipids even smaller elements like protons; makes them unique proteins, and around 800 of GPCRs are encoded in the human genome.[1] Beside that, activated G proteins are able to influence high amount of secondary messengers. It indicates they have a major impact in the cell regulation. [2]
Five protein families are targeted by drugs: GPCRs, kinases, nuclear hormone receptors, ion channels and proteases.[3] GPCR targeted drugs constitute major percentage of the therapeutic drug industry. They perceive 27% of the global market of therapeutic drugs and 34% of the total drugs -statistical data is given in 2017- approved by FDA. Approved drugs target ~100 different GPCRs. Furthermore ~300 new unapproved drugs are being tested in clinics, that target other GPCRs.[4] GPCRs vary under sub-groups depending on several features [5] ; type of the signaling molecules, homology and receptor families.[4] Mutations in GPCRs drive organisms to have numerous diseases considering to this diversity, which also leads to production and designment of different therapeutic drugs.[4] According to Figure 1, GPCR agents are mostly targeted for hypertension, allergy, schizophrenia and depression by approved drugs. In contrast diabetes, Alzheimer, asthma, Parkinson disease and obesity are the rising diseases that account for drugs in trial. It shows that GPCR based studies have a large potential to eliminate many type of diseases.[1]
Structure of GPCRs are highly convenient for designing drugs, the reason behind is the orthosteric binding site. The site is located on the extracellular side of the GPCR and it has a deep cleft. Features -shape, size and amino acid structure- of orthosteric site enable small synthetic molecules to bind with GPCR.[6] Small synthetic molecules function in two ways, by inhibiting the function of GPCR (which is mentioned as antagonists) or by triggering the activation of GPCR (which is also mentioned as agonists). Development of drug does not require additional bioengineering procedure to cross plasma membrane, since GPCRs are located in the plasma membrane of cells. Furthermore dynamic architecture of GPCR make them suitable drug targets.[1] If agonists are not present, GPCRs still have a basal activity to activate their functioning, yet activated GPCRs increase in the presence of. [1]
Additionally, GPCR targeted drugs are developed more likely for the popular diseases (allergy, hypertension, schizophrenia, depression and obesity) within the society and for the emerging novel diseases (multiple sclerosis, hypocalcaemia and smoking cessation).[4] As stated before GPCRs can be targeted for majority of the diseases and they are important elements of cells and biochemistry.
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