New Basis for Link Between Sleep and Weight

sleeping miceA number of human studies have linked lack of sleep to weight gain – decreased insulin sensitivity and glucose tolerance as well as disruption of the natural balance between the appetite hormones grehlin and leptin have been put forward to explain this link between disrupted sleep and weight gain. In studies in rodents, researchers at Merck have now shown that T-type calcium channels regulate both sleep and body weight maintenance. Mice lacking CaV3.1 T-type calcium channels were known to have altered sleep/wake patterns and the new study showed that these mice are also resistant to weight gain induced by a high fat diet.

Writing in the Journal of Clinical Investigation, the researchers report that the knock-out mice gained significantly less weight and had less body fat than their wild-type littermates when fed a high fat diet. The resistance to weight gain of the knock-out mice could not be fully explained by reduced food intake, an overall increase in activity or increased metabolic rate. TTA-A2 structureIn further studies, a selective T-type channel antagonist, TTA-A2, was shown to prevent, and even reverse, weight gain induced by a high fat diet, and also to improve body composition to greater extent than the widely used appetite suppressant, fenfluramine. TTA-A2, when dosed either prior to the sleep phase or during the wake phase, was found to promote sleep – a result which was unexpected since the knock-out mice have increased wake time compared with wild type animals. Although the reasons for the observed differences between pharmacological antagonism and genetic knock-out remain to be fully explained, the study highlights the potential for antagonism of T-type calcium channels as a novel weight loss strategy.

The authors suggest that the benefits of T-type calcium channel antagonists may be the result of better alignment of feeding patterns and the circadian rhythm and that sleep or circadian treatments may be of particular benefit for people struggling to lose weight or maintain weight loss because of poor diet.

Pain Target Linked to Cancer

Blockade of the transient receptor potential vanilloid channel, TRPV1, which is widely expressed in both central and peripheral nervous tissue, has been considered by many groups to be an attractive approach to pain relief. chilli pepperThe receptor is activated by a number of endogenous and exogenous stimuli including the endocannabinoid, anandamide; capsaicin, the ‘hot’ component of chilli peppers; low pH; and heat. The sensitivity of TRPV1 to heat has suggested a role in maintenance of body temperature, and clinical trials of at least one TRPV1 antagonist were stopped because of unacceptable levels of hyperthermia.

A new study published in the January 19th Online First edition of the journal Cancer Research now suggests a link between TRPV1 and the development of cancer. The authors show that TRPV1 interacts with epidermal growth factor receptor (EGFR), a receptor tyrosine kinase that is overexpressed in many human epithelial cancers. Interaction of TRPV1 with EGFR was found to recruit the ubiquitin ligase, Cbl, leading to ubiquitylation and lysosomal degradation of EGFR.

In a further set of experiments, the authors showed that mouse epidermal cells over-expressing TRPV1 were significantly less likely to undergo malignant transformation when stimulated with EGFR, either with or without a tumour promoter. TRPV1 was next shown to be expressed in the skin of wild type mice but not TRPV1 knock-out mice; the knock-out mice also had elevated levels of EGFR protein in the skin. When exposed to the tumour initiator, 7,12-dimethylbenz[a]anthracene (DMBA) and the promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), almost all TRPV1 knock-out mice developed larger and more numerous tumours than age- and sex-matched wild type animals. Pretreatment of all mice with the EGFR antagonist, AG1478, significantly suppressed tumour formation, but the effect was much greater in the TRPV1 knock-out animals.

The authors suggest that channels such as TRPV1 are able have a direct effect which is independent of their function as ion channels; the TRP family of proteins seems to show different levels of expression in cancer tissues, although whether these changes are cause or effect is not known.

Purinergic Receptors in the Balance

scalesP2X7 receptors are cation-permeable, ATP-gated ion channels found on cells of immunological origin, including peripheral macrophages and glial cells in the CNS. Studies in P2X7 receptor knockout mice have suggested a specific role in inflammatory and neuropathic pain states, and there has been considerable interest in developing P2X7 receptor-selective antagonists for the treatment of inflammatory conditions and pain.

A report in the Oct 22 early edition of PNAS, however, suggests that direct blocking of P2X7 receptors may not be the best strategy for reducing pain or lessening neuronal degeneration. The report shows that P2X7 receptors in satellite cells play a crucial role in maintaining proper P2X3 receptor expression in dorsal root ganglia. Reducing P2X7 receptor expression using siRNA, or blocking P2X7 receptor activity by antagonists, was found to cause up-regulation of P2X3 receptors, leading to increased activity of sensory neurons responding to painful stimuli and evoking abnormal nociceptive behaviours in rats.

New Results for PTC124 in Cystic Fibrosis

Cystic fibrosis (CF) is a hereditary disease characterised by the production of thick sticky mucus which results in frequent lung infections. CF is caused by any one of a number of mutations in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR) which encodes a protein that transports chloride ions across cell membranes. In about 10% of patients worldwide, and more than 50% of patients in Israel, CF is caused by nonsense mutations in the messenger RNA for CFTR. Premature stop codons prevent production of functional full-length protein: patients with nonsense-mutation CF produce very little functional CFTR and often have a severe form of CF.

New Phase II results published in The Lancet show that an orally bioavailable small molecule demonstrates activity in nonsense-mutation CF. PTC124 was designed to induce ribosomes to selectively read through premature stop codons to produce functional CFTR. The data show that treatment with PTC124 results in statistically significant improvements in the chloride channel function of patients.

Nonsense mutations account for a significant number of cases of most inherited diseases and PTC124 may have the potential to treat diseases other than CF.