Allosteric modulation refers to the concept that proteins could exist in multiple conformational states and that binding of allosteric ligands alters the energy barriers or “isomerization ...coefficients” between various states. In the context of ligand gated ion channels such as nicotinic acetylcholine receptors (nAChRs), it implies that endogenous ligand acetylcholine binds at the orthosteric site, and that molecules that bind elsewhere on the nAChR subunit(s) acts via allosteric interactions. For example, studies with the homomeric α7 nAChRs indicate that such ligand interactions can be well described by an allosteric model, and that positive allosteric effectors can affect energy transitions by (i) predominantly affecting the peak current response (Type I profile) or, (ii) both peak current responses and time course of agonist-evoked response (Type II profile). The recent discovery of chemically heterogeneous group of molecules capable of differentially modifying nAChR properties without interacting at the ligand binding site illustrates the adequacy of the allosteric model to predict functional consequences. In this review, we outline general principles of the allosteric concept and summarize the profiles of novel compounds that are emerging as allosteric modulators at the α7 and α4β2 nAChR subtypes.
The adenine model of kidney disease typically involves dietary delivery of adenine over several weeks. This model can be variable in its disease progression and can result in significant mortality. ...In the current study, the amount of adenine delivered to rats was controlled by utilizing oral gavage administration over a short period in an attempt to induce robust renal pathology while addressing variability and viability of the animals.
Adenine (150 or 200 mg/kg) was administered via oral gavage for 10 consecutive days, and assessed over a total of 20 days.
Both adenine dose groups manifested pathophysiological features of kidney disease such as proteinuria, elevated serum creatinine and BUN, and tubulointerstitial fibrosis. The animals also displayed a decline in glomerular filtration rate. Renal mRNA expression of genes associated with injury, inflammation, and fibrosis (i.e., Col1a1, Acta2, Serpine1, Timp1, Fn-Eda, Tgfb1, Ccl2, Nlrp3, Aqp1 and Ccnd1) were elevated as were urinary biomarkers that have translational utility (i.e., clusterin, KIM-1, MCP-1, OPN, NGAL, B2M, calbindin, and cystatin C). All disease endpoints were more pronounced in the 200 mg/kg group, however, while measures of tissue fibrosis were sustained, there was partial recovery by day 20 in functional readouts. No mortality was observed in either dose group.
Short-term delivery of adenine via precise gavage delivery induced a robust model with hallmarks of fibrotic kidney disease, had limited variance between animals, and no animal morbidity within the 20 days studied. This model represents a methodical alternative to long-term dietary dosing of adenine.
Potassium channels play important roles in vital cellular signaling processes in both excitable and nonexcitable cells. Over 50 human genes encoding various K(+) channels have been cloned during the ...past decade, and precise biophysical properties, subunit stoichiometry, channel assembly, and modulation by second messenger and ligands have been elucidated to a large extent. Recent advances in genetic linkage analysis have greatly facilitated the identification of many disease-producing loci, and naturally occurring mutations in various K(+) channels have been identified in diseases such as long-QT syndromes, episodic ataxia/myokymia, familial convulsions, hearing and vestibular diseases, Bartter's syndrome, and familial persistent hyperinsulinemic hypoglycemia of infancy. In addition, changes in K(+) channel function have been associated with cardiac hypertrophy and failure, apoptosis and oncogenesis, and various neurodegenerative and neuromuscular disorders. This review aims to 1) provide an understanding of K(+) channel function at the molecular level in the context of disease processes and 2) discuss the progress, hurdles, challenges, and opportunities in the exploitation of K(+) channels as therapeutic targets by pharmacological and emerging genetic approaches.
Abstract The α7 nicotinic acetylcholine receptor (α7 nAChR) plays a fundamental role in Ca2+ -dependent activation of signaling pathways that can modulate intracellular events involved in learning ...and memory. Activation of extracellular signal-regulated kinase-1 and -2 (ERK1/2) are well documented Ca2+ signaling events, but these have not been well characterized in response to α7 nAChR-selective ligands. The present study examined activation of ERK1/2 and explored pathways leading to CREB phosphorylation utilizing α7 nAChR-selective ligands in PC12 cells endogenously expressing α7 nAChRs. Robust concentration-dependent increase in ERK1/2 phosphorylation was triggered by structurally diverse α7 nAChR agonists such as nicotine, choline, GTS-21, SSR-180711A and PNU-282987 in the presence of the positive allosteric modulator (PAM) PNU-120596. This effect was attenuated by selective α7 nAChR antagonists or by chelation of extracellular Ca2+ . ERK1/2 phosphorylation was also attenuated by inhibitors of calmodulin-dependent protein kinase II (CaMKII), p38 MAP kinase and mitogen-activated protein kinase kinase1/2 (MEK1/2), indicating the involvement of these kinases upstream of ERK1/2. This was confirmed by direct measurement of p38 MAPK and MEK1/2 phosphorylation. These data suggest that α7 nAChR agonist-triggered Ca2+ transient in PC12 cells induces activation of CaMKII, leading to sequential phosphorylation of p38 MAPK, MEK1/2, ERK1/2 and CREB. Such mechanisms may endow the α7 nAChRs with roles in modulating Ca2+ -dependent intracellular second messenger events implicated in diverse aspects of cognition.
The acceptance of refugees and internally displaced persons represents the altruism of the countries of South Asia, which has witnessed the phenomenon of displaced persons since the early 19th ...century. The refugee phenomenon has a causal nature and will remain for a long time to come. The refugee situation in South Asia since 1947 has also resulted in protracted internal security conditions in India, Pakistan, Nepal, Sri Lanka and Bangladesh. The dual paradigm of refugees for a host country – societal concerns and security issues – can be resolved by adopting the Kautilyan Arthashastra (a treatise written around the turn of 4 BC) model of empowerment and integration for outsiders and his philosophy on securing society both from external and internal threats. Modern thinkers such as Plessner on anthropological behaviour, and critical security theories by Welsh and Booth, corroborate the ideas of Arthashastra. Given the prevailing global perception of refugees, the UNHCR articulation of durable solutions with a multilateral framework of understanding (MFU) among nations is a viable long-term solution. Given the peculiarities of South Asian economies, the article recommends that the long-term answer to the refugee crisis lies in an empowerment model and within the framework of collective decision-making of regional institutions such as BIMSTEC/SAARC for a coordinated and cooperative platform.
The discovery of a series of pyrrole-sulfonamides as positive allosteric modulators (PAM) of α7 nAChRs is described. Optimization of this series led to the identification of 19 (A-867744), a novel ...type II PAM with good potency and selectivity. Compound 19 showed acceptable pharmacokinetic profile across species and brain levels sufficient to modulate α7 nAChRs. In a rodent model of sensory gating, 19 normalized gating deficits. These results suggest that 19 represents a novel class of molecules capable of allosteric modulation of the α7 nAChRs.
Abstract β-Amyloid peptide 1–42 (Aβ1–42 ) is generated from amyloid precursor protein (APP) and associated with neurodegeneration in Alzheimer's disease (AD). Aβ1–42 has been shown to be cytotoxic ...when incubated with cultured neurons. However, APP transgenic mice over-expressing Aβ1–42 do not show substantial loss of neurons, despite deficits in learning and memory. It is thus emerging that Aβ1–42 -induced memory deficits may involve subtler neuronal alternations leading to synaptic deficits, prior to frank neurodegeneration in AD brains. In this study, high content screen (HCS) microscopy, an advanced high-throughput cellular image processing and analysis technique, was utilized in establishing an in vitro model of Aβ1–42 -induced neurotoxicity utilizing rat neonatal primary cortical cells. Neurite outgrowth was found to be significantly reduced by Aβ1–42 (300 nM to 30 μM), but not by the scrambled control peptide control, in a time- and concentration-dependent manner. In contrast, no reduction in the total number of neurons was observed. The Aβ1–42 -induced reduction of neurite outgrowth was attenuated by the NMDA receptor antagonist memantine and the α7 nicotinic acetylcholine receptor (nAChR) selective agonist PNU-282987. Interestingly, the α7 nAChR antagonist methyllycaconitine also significantly prevented reduction in Aβ1–42 -induced neurite outgrowth. The observed neuroprotective effects could arise either from interference of Aβ1–42 interactions with α7 nAChRs or by modification of receptor-mediated signaling pathways. Our studies demonstrate that reduction of neurite outgrowth may serve as a model representing Aβ1–42 -mediated neuritic and synaptic toxicity, which, in combination of HCS, provides a high-throughput cell-based assay that can be used to evaluate compounds with neuroprotective properties in neurons.
The well-known interferon-inducer tilorone was found to possess potent affinity for the agonist site of the α7 neuronal nicotinic receptor (Ki=56nM). SAR investigations determined that both basic ...sidechains are essential for potent activity, however active monosubstituted derivatives can also be prepared if the flexible sidechains are replaced with conformationally rigidified cyclic amines. Analogs in which the fluorenone core is replaced with either dibenzothiophene-5,5-dioxide or xanthenone also retain potent activity.