Current Molecular Pharmacology - Volume 2, Issue 3, 2009

Estrogens are hormones that modulate a diverse array of effects during development and adulthood. The effects of estrogen are mediated by two estrogen receptor (ER) isotypes, ERa and ERa, which classically function as transcription factors to modulate specific target gene expression and in addition regulate a growing list of intracellular signaling cascades. These receptors share protein sequence homology and protein-motif organization but have distinct differences in their tissue distribution and binding affinities for their ligands. In the nervous system estrogen has been implicated to play a role in a number of processes which regulate synaptic plasticity including synaptogenesis and neurogenesis. The role for estrogen in a range of neurological and neuropsychiatric diseases is also becoming very apparent. Estrogen is able to regulate processes and behaviours relevant for both Alzheimer's disease and schizophrenia and to modulate neuroendocrine and inflammatory processes important in neuroinflammation, anxiety and depressive disorders as well as chronic pain. We will consider the rationale for estrogen-based therapies for diseases of the nervous system. In particular we will highlight the molecular mechanisms and signal transduction pathways most likely underlying the effects of estrogen in the CNS.

The superfamily of G protein coupled receptors (GPCRs) comprises the largest group of cell surface receptors expressed by the human genome. Accordingly, these receptors are the target of a substantial portion of current pharmaceuticals. Over the past few decades there have been many substantial discoveries regarding GPCRs structure and function that have led to the current understanding of the complexity of the signal transduction which these receptors initiate. What was once generally believed to be a simple linear pathway, has become one with manifold bifurcations and multiple regulatory and feedback mechanisms. In the following we review the fundamental ground work upon which this field of research was established and the work that has more recently begun to uncover the complexity of GPCR signaling. The emerging signaling paradigm includes (i) the capacity of one receptor to couple to and initiate pathways through multiple G proteins, (ii) the capability of one G protein to activate many effectors, as well as (iii) the ability of a GPCR to transduce signals through G protein independent pathways. We also briefly touch upon some implications of GPCR oligomerization and discuss signaling cascades of two serotonin receptors, 5-HT4 and 5-HT7, whose pathways exemplify the richness and complexity of GPCR signaling mechanisms.

Obesity is an important health problem because it is associated with diseases such as type 2 diabetes, hypertension, and hyperlipidemia in metabolic syndrome. The detail molecular mechanisms that underlie obesity have not been fully elucidated, and its therapeutic approach is of general interest. There is increasing evidence that obesity is under control of several factors in the brain and a number of studies have revealed that the brain functions that regulate energy balance play a central role in the development of obesity. Several orexigenic and anorexigenic neuropeptides in the brain are involved in obesity, although their relative contributions are different. The histamine-containing neurons and its receptors are distributed throughout the brain. The results of pharmacological studies revealed that neuronal histamine and its receptors are involved in the regulation of obesity in rodents and humans. In this review, we describe the neuronal histamine and its receptor as a pharmacological molecular target for obesity.

X-ray structures of molluscan acetylcholine-binding proteins and procaryotic proton-activated ion channels (ELIC and GLIC) enable us to model the ligand binding and activation mechanism of ligand-gated pentameric ion channels. Common versus distinct features can be deduced from the binding of agonists, antagonists and allosteric modulators in subunit interfaces of nicotinic acetylcholine, A-type γ-aminobutyric acid, glycine and 5-HT3-type serotonin receptors. Ligand interactions in subunit interfaces elicit conformational waves from the closure of the agonist-binding cavity through binding loops, ß-strands and transmembrane helices to pore gating.

Glioblastoma Multiforme (GBM) tumors are the most common type of brain tumors. These tumors are in general very malignant and can be characterized as rapidly progressive astrocytomas. The pathological characteristics of these tumors are exemplified by an active invasiveness, necrosis and a specialized form of angiogenesis, known as microvascular hyperplasia. These pathological features are thought to be due to tissue hypoxia. Cells that are under hypoxic stress can either develop an adaptive response that includes increasing the rate of glycolysis and angiogenesis or undergo cell death by promoting apoptosis and/or necrosis. The ability of tumor cells to maintain a balance between an adaptation to hypoxia and cell death is regulated by a family of transcription factors called hypoxia-inducing factors (HIF), which are essential for the regulation of the expression of a large number of hypoxia-responsive genes. The hypothesis that tumor hypoxia would facilitate the likelihood of metastases, tumor recurrence, resistance to chemotherapy and radiotherapy and the invasive potential; all of which culminate in a decrease in patient survival. In this review we will summarize the role of hypoxia in GBM with regard to drug therapy and toxicity and attempt to describe the possible interactions between hypoxia and apoptosis.

Guanylyl cyclase C (GCC) is the receptor specifically expressed by intestinal cells for the paracrine hormones guanylin and uroguanylin and diarrheagenic bacterial heat-stable enterotoxins. This tissue-specific receptor coordinates lineage-dependent regulation of epithelial homeostasis, and its disruption contributes to intestinal tumorigenesis. It coordinates regenerative and metabolic circuits by restricting the cell cycle and proliferation and programming metabolic transitions central to organizing the dynamic crypt-surface axis. Further, mice deficient in GCC signaling are more susceptible to colon cancer induced by Apc mutations or the carcinogen azoxymethane. Moreover, guanylin and uroguanylin are gene products most commonly lost, early, in colon cancer in animals and humans. The role of GCC as a tumor suppressing receptor regulating proliferation and metabolism, together with the universal loss of guanylin and uroguanylin in tumorigenesis, suggests a model in which colorectal cancer is a paracrine hormone deficiency syndrome. In that context, activation of GCC reverses the tumorigenic phenotype by limiting growth of colorectal cancer cells by restricting progression through the G1/S transition and reprogramming metabolic circuits from glycolysis to oxidative phosphorylation, limiting bioenergetic support for rapid proliferation. These observations suggest a pathophysiological hypothesis in which GCC is a lineage-dependent tumor suppressing receptor coordinating proliferative homeostasis whose dysregulation through hormone loss contributes to neoplasia. The correlative therapeutic hypothesis suggests that colorectal cancer is a disease of hormone insufficiency that can be prevented or treated by oral supplementation with GCC ligands.