Towards an understanding of the molecular mechanisms that underlie the function of vascular ATP-sensitive potassium (KATP) channels

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High blood pressure is a risk factor for stroke and heart disease from which billions of people are suffering. Blood pressure is regulated by the diameter of the arteries through which the blood flows around the body. The diameter of these vessels is actively controlled by a surrounding layer of smooth muscle cells. Contraction of vascular smooth muscle narrows the arterial diameter and increases blood pressure. Conversely, its relaxation lowers blood pressure. On the inner wall of the artery is a layer of endothelial cells that regulate the function of smooth muscle. One of the important regulators of the contraction/relaxation process in vascular smooth muscle cells is a class of proteins known as ion channels, tiny gated pores that allow ions (such as potassium) to move into and out of the cell. The ATP-sensitive potassium (KATP) channels play a particularly important role in regulating the function of the cardiovascular system. A key feature of these channels is that their opening and closing is regulated by changes in the metabolic state of the cell. This is because they are modulated by the intracellular concentration of ATP, the molecule that serves as the energy currency of the cell. In the heart, KATP channels are especially active in times of cardiac stress, such as when blood flow is compromised (ischemia), and they help to protect against heart attack. In smooth muscle, however, they are important in regulating the resting level of vessel tone, and thus the diameter of the blood vessel. When these pores are open, vascular smooth muscle cells relax, lowering the blood pressure; when they are closed, contraction is favoured and blood pressure increases. Mice that lack KATP channels can die from a type of coronary vasospasm known as Prinzmetal syndrome that is also found in humans. It is therefore very important to understand how the opening and closing of the KATP channel is regulated. The aim of my studies is to determine the molecular mechanisms that underlie the function of vascular KATP channels, to elucidate how these are regulated by the energy metabolism of the cell, and to explore how mutations in KATP channel genes cause vascular disorders. I will use a number of experimental techniques to address these questions: from measurement of the passage of ions through a single ion channel to genetic modification of the KATP channel. I will also explore how drugs regulate vascular KATP channels. Such studies will provide us with a better understanding of how this channel operates under normal conditions and what goes wrong in disease states. They may also facilitate the development of novel drugs for the treatment of cardiovascular diseases such as hypertension and angina.