Cell's 'dustbin' is vital pathway

The elements of a new pathway likely to be involved in most body functions – from blood flow to metabolism and fertilisation of egg cells – have been identified by an international team in which researchers in the Department of Pharmacology took a leading role.

The discovery, reported in Nature, could provide new targets for drug development for diabetes, heart abnormalities, and many other conditions.

‘Calcium plays a vital role in the body,’ says Dr John Parrington. ‘And it’s not all about building healthy bones and teeth. Calcium is used to coordinate and control many different events, responses and reactions in the body.’

Bodily processes as diverse as heart contraction, nerve growth, control of appetite, regulation of the immune system, and insulin secretion by the pancreas are mediated by calcium. Each of these processes requires cells to have a coordinated, measured, and timed response. And cells use calcium to achieve this.

Calcium ions are released from stores within cells in response to signals from hormones or other chemicals in the blood, and the sudden increase in the amount of calcium present triggers the right physiological response – whether that’s contraction of a heart muscle cell or release of insulin by a cell in the pancreas. Of course, when this process gets disrupted, it can lead to a range of different conditions.

It’s in our basic understanding of how these chemical messages mediate important physiological events in the body at the molecular level, that Professor Antony Galione and John Parrington, along with researchers at the University of Edinburgh and colleagues in the US, have made a breakthrough.

The release of calcium from stores in the cell can be triggered by three different chemical signals or messengers. They are called IP3, cADPR and NAADP. The IP3 system is well known, and that involving cADPR is partially understood. What the Oxford team has done is reveal exactly how the chemical messenger NAADP has an effect. Previously this was entirely unknown.

The team identified a set of protein channels that sit in a compartment of the cell called the lysosome. (This is interesting in itself, as the lysosome was previously thought of pretty much as a dustbin in which unwanted substances were broken down.) They have shown that NAADP triggers the protein channels to release calcium held within the lysosome.

‘It's been a bit of a detective story. We knew that there was this chemical NAADP and we had proposed from our earlier studies that it released calcium from lysosomes. However, our discovery of a new class of calcium release channel opened by NAADP on the lysosome really has been the acid test,’ says Antony Galione, who is head of the Department of Pharmacology. ‘This opens an entirely new chapter in calcium signalling, which is important since most cellular activities are either directly or indirectly controlled by calcium.’

‘Now with the identity of the NAADP receptor uncovered, the possibility of designing new drugs to combat conditions such as diabetes, obesity and abnormalities of the heart and immune system, have been greatly advanced,’ adds John Parrington. They are already beginning to reveal the potential for human health, showing that the newly identified channel is critical.

‘”Knockout” mice, from which the gene for the protein channel has been deleted, show abnormal NAADP-induced calcium signals in the pancreatic cells that secrete insulin in response to blood sugar levels,’ explains John Parrington. ‘This finding could have great relevance for understanding conditions such as diabetes.’

The hope now is that drugs can be designed to target the protein channel in the appropriate way and restore its function where it is impaired.