The role of heme in ion channel function

The involvement of the metallic element iron in various biological systems is well known. In many cases, iron is employed in the form of a heme group, most famously in hemoglobin. The family of heme proteins is vast, and the involvement of heme in these proteins is as a prosthetic group, in which the heme is tightly associated with the protein structure. Extensive studies have shown that the binding of heme to a particular protein defines the reactivity of that molecule. In this way a large number of biological requirements - such as oxygen transport, catalytic oxidation of all kinds of substrates, synthesis of NO, electron transfer etc - become accessible through incorporation of the same heme group into different protein structures.

Very recently, it is becoming clear that the description above represents only a small part of a much more complex biological role for heme and that other, regulatory roles for heme have been overlooked. One example is in the regulation of ion channel function. Ion channel proteins form a pore through which ions (e.g. potassium, calcium, sodium) can travel through cell membranes. These channels have gates that open and close, and thus regulate the flow of ions through the pore. This ion flow governs many important biological processes such as beating of the heart and brain function. There is emerging evidence that heme can control opening and closing of these ion channel gates. Through a collaboration with the established cell physiology group at Leicester, and by incorporation of computational and proteomic approaches, we intend to build a more detailed description of how heme exerts these regulatory effects in a number of different ion channels.

At the heart of this proposal is the hypothesis that heme acts as an important intracellular signalling messenger in biology. Specifically, we are interested in the effects of changes in intracellular heme concentration on ion channel function and our preliminary data have identified clear interactions between heme and channel proteins. These data chime with evidence emerging recently from other laboratories. At the moment, there is no information on how this regulatory control is achieved: this represents a major gap in our understanding that we intend to address.

We intend to test the specific effects of heme in two classes of potassium channels and are uniquely placed to do so because our experimental approach couples existing reductionist approaches in protein structure and mechanism with electrophysiology methods that measure channel function in the cellular environment. These experimental studies will be integrated with computational and proteomics approaches to build a molecular-level picture of the heme-based regulatory process and the role of heme binding proteins.

The work is genuinely timely since very little is yet known about the molecular mechanisms involved in heme regulation of ion channels and we expect to be able to make a major impact in this area.

WHO WILL BENEFIT FROM THE RESEARCH?

There are numerous beneficiaries.

1. The immediate existing personnel working with the PI and CIs will benefit directly, through interactions with the project and the personnel hired on the project. This comes in the form of expertise swapped between personnel, shared working habits, group meetings, shared learning, future collaborations between personnel once they have left the project etc.

2. The Departments involved, plus the University, also benefit. This comes through building new collaborations from outside, bringing new ideas, new ways of working, new skills, etc. The simple exchange of people across departments should not be under estimated: without it an organization becomes static, with no new input of ideas year after year. This movement of personnel is a great benefit to UK science and UK plc.

3. The wider community, who benefit in terms of seeing how the work develops and it being a stimulus for other projects, providing ideas and a source of discussion that filters in and out of Leicester and elsewhere. Funding of new projects encourages a dialogue with other users/interested parties, which sparks new ideas and innovation elsewhere.

4. First destination employers, who benefit by picking up highly-skilled staff trained in the investigators' laboratories.

5. The wider biological community, in this country and abroad who will be interested in the results (through citations etc).

6. Heme enzymes (P450s, NO synthase for example) and ion channels (especially KATP and hERG channels) are a mainstay of pharmaceutical research, and this sector depends on fundamental, molecular level information emerging from academic groups around the world to prosecute their drug discovery campaigns. Our work thus feeds directly into UK plc and the contribution of molecular-level, fundamantal studies of this kind should not be underestimated. Clearly, this has an impact on 'quality of life', since all biotech/pharma is concerned with improvement in quality of life.

HOW WILL THEY BENEFIT FROM THIS RESEARCH?

There are various routes through which this can be achieved.

Obviously, publication in open-access journals is one important way of publicizing information, plus attendance at national and international meetings, for which we have requested appropriate resource. We will be in regular contact with other stake-holders in the UK and abroad, and the PI is involved in organization of various events as on-going activities, such as mini-symposia, conferences etc. This serves to publicise our work to the widest possible audience. We also routinely send our students and PDRA onto training workshops arranged by other organizations to provide training and to disseminate our work further. We are in the habit of sending PDRAs and students to smaller meetings which the PIs and CIs cannot attend, often giving talks at these events. We also have regular seminars and small meetings/conferences at Leicester, so that the ideas are publicized informally through these channels.

The University has a Business Development Office, for encouraging engagement with industry (the PI has on-going links here).

See also Impact Statement (separate attachment).