Opposing modulation of Cx26 gap junctions and hemichannels by CO.

Key Points: A moderate increase in (55 mmHg) closes Cx26 gap junctions. This effect of CO is independent of changes in intra- or extracellular pH. The CO -dependent closing effect depends on the same residues (K125 and R104) that are required for the CO -dependent opening of Cx26 hemichannels.

Cx26 keratitis ichthyosis deafness syndrome mutations trigger alternative splicing of Cx26 to prevent expression and cause toxicity .

The Cx26 mRNA has not been reported to undergo alternative splicing. In expressing a series of human keratitis ichthyosis deafness (KID) syndrome mutations of Cx26 (A88V, N14K and A40V), we found the production of a truncated mRNA product. These mutations, although not creating a cryptic splice site, appeared to activate a pre-existing cryptic splice site.

Structural determinants of CO-sensitivity in the β connexin family suggested by evolutionary analysis.

A subclade of connexins comprising Cx26, Cx30, and Cx32 are directly sensitive to CO. CO binds to a carbamylation motif present in these connexins and causes their hemichannels to open. Cx26 may contribute to CO-dependent regulation of breathing in mammals.

The poor design of clinical trials of statins in oncology may explain their failure - Lessons for drug repurposing.

Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an "undruggable" target, suggesting that they may be usefully repurposed to treat cancer.

ABT-737 and pictilisib synergistically enhance pitavastatin-induced apoptosis in ovarian cancer cells.

There is considerable interest in redeploying drugs for use in combination with other oncology therapeutics. The single-agent activity of statins in ovarian cancer has been widely reported, however the drug concentration required to cause cell death is considerably higher than that achieved in patients receiving statin treatment for hypercholesterolemia. Unfortunately, statins can cause myopathy when administered in high doses.

Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer.

Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary.

Evolutionary adaptation of the sensitivity of connexin26 hemichannels to CO2.

CO readily combines with HO to form [Formula: see text] and H Because an increase of only 100 nM in the concentration of H (a decrease of 0.1 unit of pH) in blood can prove fatal, the regulated excretion of CO during breathing is an essential life-preserving process. In rodents and humans, this vital process is mediated in part via the direct sensing of CO via connexin26 (Cx26).

Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro.

Connexin26 (Cx26) mutations underlie human pathologies ranging from hearing loss to keratitis ichthyosis deafness (KID) syndrome. Cx26 hemichannels are directly gated by CO and contribute to the chemosensory regulation of breathing. The KID syndrome mutation A88V is insensitive to CO, and has a dominant negative action on the CO sensitivity of Cx26 hemichannels, and reduces respiratory drive in humans.