G protein coupled receptors-systems (GPCRs).Illustrative advances from cannabinoid, chemokine and

Vol. 1(1), pp. 001-007, April, 2013 Available online@http://www.uniquejournals.org/URJMMS ©2013 Unique Research Journals Unique Research Journal of Medicine and Medical Science

Review G protein coupled receptors-systems (GPCRs): Illustrative advances from cannabinoid, chemokine and melanocortins receptors

Abdelaziz Ghanemi1,2, Ling He1* and Ming Yan3 1Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

2Department of Pharmacy, Faculty of Medicine, Mentouri University of Constantine, Constantine 25000, Algeria.

3National Drug Screening Laboratory, China Pharmaceutical University, Nanjing, 210009, China.

*Corresponding author. E-mail: heling92@hotmail.com. Tel: +008613851612452. Fax: +86 2583240236. Accepted 10 April, 2013 The pharmacological targeting of the G protein coupled receptors constitutes an important therapeutic approach among the treatments of the cerebral and the neurological diseases. This importance comes from the fact that G protein coupled receptors are implicated in a variety of physiological functions. Furthermore, studies of the pathological aspects of divers diseases have revealed that G protein coupled receptors play key roles in both the pathogenesis and the prognosis of such diseases. Thus, these receptors became a large area of research in medicine, biology, pharmacology, physiology and even genetics. Herein, we have exemplified how cannabinoid, chemokine and melanocortins receptors’ systems may constitute novel targets in several diseases. The reported findings might also constitute starting points to develop new therapies that could start from the biological properties to reach pharmacological applications. Moreover, these advances may provide further elements to design new research methods and optimize laboratories approaches in both pharmacology and neurosciences.

Keywords: G protein coupled receptor (GPCR), chemokines receptor, cannabinoid receptor, melanocortins receptor, nervous system, potential target.

INTRODUCTION G protein coupled receptors (GPCR) represent the most extensively targeted protein class for marketed drugs (Topiol, 2013) and are one of the largest classes of cell-surface receptors (Santulli et al., 2013). It is estimated that 30 % of current clinical pharmaceutical agents available are ligands directed at GPCRs (Santulli et al., 2013). The GPCRs-related discoveries have a diversity of applications in many medical and even non medical fields. For instance, both neohesperidin dihydrochalcone (NHDC) and cyclamate synergistically potentiated cell response to sucrose (Schiffman et al., 1995, Birch, 1999) which is mediated via GPCRs, therefore, further investigations could allow us to reduce sugar contents in beverage and food and come out with new forms of healthy diet products and provide a starting point to develop more molecules for diabetics and other kind of metabolic disorders as well. The complex coupling and the engaged pathways make targeting GPCRs system more important. Indeed, however, the divers’ novel molecules which target GPCRs systems that provided or may provide new therapeutics remain the main researches topic of the GPCRs system and the recent findings are focusing on the high pharmacological importance of modifying such systems. Noticeable researches and publications illustrate the current status of this area. Indeed, psychiatry is among the important 002 Unique Res. J. Med. Med. Sci. fields that have benefited from the advances of the pharmacological targeting of the GPCRs (Ghanemi), 2013a). Furthermore, laboratories observations about compounds and reagents effects on cells and some GPCRs (Ghanemi), 2013b) gave indications about the potential usage of those chemicals to further develop new leads via the drug screening or via the study of the biological properties. The following examples represent selected advances that show the potential that targeting GPCRs has among the modern pharmacotherapies. By GPCRs systems we refer to the receptors, the enzymatic pathways and the biochemical reactions implicated in the related signaling mechanisms. CANNABINOID RECEPTORS SYSTEM WITH NEUROPROTECTIVE PROPERTIES? Several cognitive functions including learning, memory and neuroprotection, in addition of other neurophysiological aspects have been shown to involve both the GPCR systems of Cannabinoid receptors 1 (CB1R) and 2 (CB2R) (Matsuda et al., 1990, Howlett et al., 2002) and the extracellular signal-regulated kinases 1 and 2( ERK1 and ERK2) (Asimaki and Mangoura, 2011). CB1 receptors exist in different brain regions such as cerebral cortex, striatum, cerebellum, hippocampus and hypothalamus (Herkenham, 1991) and these receptors interact with numerous neurotransmitters (Di Marzo, 2008) thus, it is getting more importance in pharmacology and neurophysiology. Several papers pointed that CB1 receptors activate ERK (Bouaboula et al., 1995, Galve-Roperh et al., 2002, Davis et al., 2003, Derkinderen et al., 2003, Rubovitch et al., 2004). In addition, whereas cell proliferation, transformation, and apoptosis have been linked to CB1R-dependent activation of ERK(Bouaboula et al., 1995, Galve-Roperh et al., 2002), ERK activity has been linked to neuronal differentiation, synaptic plasticity and memory (Kelleher et al., 2004, Samuels et al., 2008). A recent study, that aimed to indentify the enzymatic pathway events that link CB1R to the activation of ERK in CNS neurons (Asimaki and Mangoura, 2011), has highlighted that both PKC (precisely PKCε) and Tyrosine kinases TK (including the two families tyrosine-protein kinase Src (Src), and tyrosine-protein kinase Fyn (Fyn)) are implicated in the CB1R pathway. These results are consistent with previous data. Indeed, PKCε has many roles in CNS including learning and memory and in synaptic remodeling (Hama et al., 2004). It has also been found prominently in differentiating and differentiated neurons (Prekeris et al., 1996, Mangoura et al., 2006) supposing a role in neuron differentiation. Furthermore, numerous studies have linked CB1Rs with PKC activity (Hillard and Auchampach, 1994, Rubovitch et al., 2004, Wallace et al., 2009). On the other hand, other publications have indicated that GPCR signaling may involve tyrosine kinases(Ma et al., 2000, Amorino et al., 2007) (Mangoura and Dawson, 1993, Rodriguez-Fernandez and Rozengurt, 1996, Mangoura, 1997, Sandilands et al., 2007) and the same enzyme(PKC) was precisely shown to play a role in CB1R activity (Galve-Roperh et al., 2002; Derkinderen et al., 2003; Hart et al., 2004; Rubovitch et al., 2004; He et al., 2005). Recently, the CB₂ cannabinoid receptor ligands 4-Oxo-1,4-dihydropyridines have shown a protection against experimental colitis (El Bakali et al., 2012) and both albuminuria and podocyte protein loss can be ameliorates by CB2 activation (Barutta et al., 2011). Furthermore, CB2R Agonist may ameliorate Alzheimer-Like Phenotype (Aso et al., 2013) . Taken together, these new elements illustrate the neuroprotective properties of CB1R and the enzymes implicated in its pathway (ERK, PKC and TK), that are the elements via which the signal is transferred from the GPCR to the endocellular medium, and how they are linked with several neurofunctions such us learning and memory; in addition of some neurophysiological processes including cell proliferation, transformation and synaptic plasticity. Therefore, targeting CB1R or the related enzymatic arsenal may provide new therapeutic agents for CNS-related diseases, mainly those with neurodegenerative components and those with the loose of cognitive functions as symptoms. Although, herein we provide a starting point yet deeper researches and investigations are still required.