Current Molecular Pharmacology - Volume 5, Issue 3, 2012

Heptahelical G protein-coupled receptors, such as the β-adrenergic and the angiotensin II type 1 receptors, are the most diverse and therapeutically important family of receptors in the human genome, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by phosphorylation of the agonist-bound receptor by the family of G-protein coupled receptor kinases (GRKs), with GRK2 being its most prominent member, followed by βarrestin binding, which uncouples the phosphorylated receptor and G protein and subsequently targets the receptor for internalization. As the receptor-βarrestin complex enters the cell, βarrestins serve as ligand-regulated scaffolds that recruit a host of intracellular proteins and signal transducers, thus promoting their own wave of signal transduction independently of G-proteins. A large number of preclinical studies in small and large animals over the past several years have pinpointed specific pathophysiologic roles played by these two families of receptor-regulating proteins in various cardiovascular diseases, directly implicating them in disease pathology and suggesting them as potential therapeutic targets. The present review gives an account of what is currently known about the benefits of cardiac and adrenal GRK2 inhibition for cardiovascular disease treatment, and also discusses the exciting new therapeutic possibilities emerging from uncovering the physiological roles of βarrestin-mediated signaling in vivo in the cardiovascular system.

Tumourigenesis is regulated by the complex cell-matrix signalling interactions that incorporate feedback mechanisms from constantly evolving microenvironments. Under normal circumstances, these matrix signalling processes together with infiltrating immune cells tightly control the extent of tissue remodelling. They are the key elements of regulated homeostatic repair of local matrix architecture and biological function. In contrast, the pathological tumourigenesis employing similar mechanisms and cellular components to change cellular phenotype promoting proliferation and transformation. However, there is a significant knowledge gap in our understanding about the network integration of different matrix induced signalling processes and their connection to drug side effects. Using epithelial tumourigenesis as a model system, we show that drug actions and pathological conditions are associated with crosstalk signalling mechanisms. These processes functionally integrate microenvironmental cues and generate representative gene expression profiles that are different from those induced by the native ligand-driven signalling mechanisms. Particularly in this review, we are focusing on crosstalk signalling processes that are sensitive to transforming growth factor receptor type I (TβRI) inhibitor A83-01 (3-(6-Methyl-2-pyridinyl)-N-phenyl-4-(4-quinolinyl)-1H-pyrazole- 1-carbothioamide). This process is affecting inflammatory gene expression, epithelial to mesenchymal transition, migration, proliferation, and changes in metastatic gene expressional patterns. As a result, phenotypic and functional modifications to cells and their immediate microenvironments are unavoidable. Here we demonstrate that future screening strategies for unintended drug side effects from molecular to systemic levels would benefit from future crosstalk signalling analysis. Thorough analysis could be used to forecast the diverse and highly variable gene expression patterns caused by pathological microenvironmental conditions which become apparent only in larger patient populations.

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of catecholaminergic neurons in several brain regions. The motor symptoms of the disease are related to degeneration of the midbrain dopaminergic neurons, which occurs some time after the disease has begun. Both the innate and adaptive immune systems appear to play a role in the neurodegenerative process, and may contribute to disease progression. Here we review the neuropathology of PD with attention focused on the involvement of the innate immune cells (microglia) and the adaptive immune cells (T lymphocytes). In addition, we discuss animal models of the disease with emphasis on a progressive rat model which allows a detailed analysis of how the immune system contributes to neurodegeneration both during early and late stages of degeneration. Finally, for the early detection and treatment of PD, we discuss immunotherapy approaches.

G-protein coupled receptors (GPCRs) are seven transmembrane receptors that are pivotal regulators of cellular responses including vision, cardiac contractility, olfaction, and platelet activation. GPCRs have been a major target for drug discovery due to their role in regulating a broad range of physiological and pathological responses. GPCRs mediate these responses through a cyclical process of receptor activation (initiation of downstream signals), desensitization (inactivation that results in diminution of downstream signals), and resensitization (receptor reactivation for next wave of activation). Although these steps may be of equal importance in regulating receptor function, significant advances have been made in understanding activation and desensitization with limited effort towards resensitization. Inadequate importance has been given to resensitization due to the understanding that resensitization is a homeostasis maintaining process and is not acutely regulated. Evidence indicates that resensitization is a critical step in regulating GPCR function and may contribute towards receptor signaling and cellular responses. In light of these observations, it is imperative to discuss resensitization as a dynamic and mechanistic regulator of GPCR function. In this review we discuss components regulating GPCR function like activation, desensitization, and internalization with special emphasis on resensitization. Although we have used β-adrenergic receptor as a proto-type GPCR to discuss mechanisms regulating receptor function, other GPCRs are also described to put forth a view point on the universality of such mechanisms.

microRNA(miRNA) is a kind of non-coding RNA that has a regulatory function on coding RNA. miRNA can target the 3' UTR of mRNA and inhibit its gene expression by either inhibiting its translation or promoting its degradation. miRNAs are thus considered to be oncogenic or antineoplastic, depending on their downstream target mRNAs. Besides their clinical application in cancer treatment, diagnosis, and prognosis, miRNA has also recently been reported to be involved in cancer chemotherapy and chemoprevention. This review focuses on the implication of miRNA in cancer chemoprevention and cancer control as well as molecular mechanisms underlying those biological effects.

In 1994, the isolation of an opioid receptor-related clone soon led to the isolation and characterization of a novel neuropeptide, termed nociceptin or orphanin FQ (N/OFQ). This heptadecapeptide binds to the N/OFQ receptor (NOP) with high affinity, but does not interact directly with classical opioid receptors. The regional distribution of N/OFQ and of its receptor suggest any possible involvement of this neurotransmission system in motor and balance control, reinforcement and reward, nociception, stress response, sexual behavior, aggression and autonomic control of physiological processes as well as of immune functions. The actions of N/OFQ may also be uniquely dependent on contextual factors, both genetic and environmental. As for most of the G protein coupled receptors, NOP C-terminal sequences are believed to interact with proteins that are mandatory for anchoring receptor at the plasma membrane, internalization, recycling, or degradation after ligand binding. Increasing details of how NOP receptors are activated and removed from the plasma membrane have been elucidated in vitro, and more importantly in a physiological context. Details of how these receptors travel and recycle following internalization have also shed light on the importance of such mechanisms for any potential therapeutic use of NOP ligands. A picture of the pathways and proteins involved in these processes is beginning to emerge. This review will address molecular events contributing to NOP receptor signaling and trafficking.

The incidence of central nervous system (CNS) metastases secondary to solid tumors is increasing. As more effective systemic therapy is being used in patients with solid tumors, patients with cancer live longer and are ultimately at higher risk for CNS metastases. However, CNS metastases remain challenging to treat because of limited available therapeutic options. This article reviews mechanisms of CNS metastases, the use of bevacizumab and other angiogenesis inhibitors in the treatment of recurrent and front-line CNS metastases, as well as emerging issues of resistance to antiangiogenic therapy.

Estrogens have been recently postulated as potential agents in the development and progression of prostate cancer. Previous studies have demonstrated presence of both variants of estrogen receptor (ER); ER alpha (ERα) and ER beta (ERβ) in differing proportions between normal prostate and prostate cancer. It has been previously suggested that estrogens may either accelerate or inhibit growth of prostate cancer cell growth, depending on ER status. In particular, ERβ is considered to have a growth inhibitory role in prostate tissue. ERβ is significantly expressed in human prostate cancer cells, and hence it is considered a key factor for anti-cancer therapy. Therefore, various types of ERβ ligands have been investigated to clarify the mechanism of ERβ-mediated pathway of inhibitory effects on prostate cancer cells. Herein, we review recent examinations of ERs in prostate cancer, and the significance of ER mediated signaling pathways, with a focus on ERβ, as prospective therapeutic targets in prostate cancer.