Chapter 5 Molecular Cardiovascular Medicine
In the past decades we have witnessed what may well be termed a revolution in the biomedical sciences, as molecular methodologies have suddenly become more evident on the clinical scene. Molecular biology originated in the 1950s, its birth most commonly identified with the description of the structure of deoxyribonucleic acid (DNA) by Watson and Crick.1
MACHINERY BEHIND THE CARDIAC RHYTHM: ION CHANNELS
The cardiac action potential results from the flow of ions through ion channels, which are the membrane-bound proteins that form the structural basis of cardiac electrical excitability. In response to changes in electrical potential across the cell membrane, ion channels open to allow the passive flux of ions into or out of the cell along their electrochemical gradients. Ion flux results in a flow of current, which displaces the cell membrane potential toward the potential at which the electrochemical gradient for the ion is zero, called the equilibrium potential (E) for the ion. Depolarization of the cell could, in principle, result from an inward cation current or an outward anion current; for repolarization the reverse is true. In excitable cells, action potentials are mainly caused by the flow of cation currents. Membrane depolarization results principally from the flow of Na+ down its electrochemical gradient (ENa is around +50 mV), whereas repolarization results from the outward flux of K+ down its electrochemical gradient (EK is around −90 mV). Opening and closing of multiple ion channels of a single type result in an individual ionic current. The integrated activity of many different ionic currents, each activated over precisely regulated potential ranges and at different times in the cardiac cycle, results in the cardiac action potential (Box 5-1).
Phase 0: The Rapid Upstroke of the Cardiac Action Potential
The rapid upstroke of the cardiac action potential (phase 0) is caused by the flow of a large inward Na+ current (INa) (Box 5-2). INa is activated by depolarization of the sarcolemma to a threshold potential of −65 to −70 mV. INa activation, and hence the action potential, is an all-or-nothing response. Subthreshold depolarizations have only local effects on the membrane. After the threshold for activation of fast Na+ channels is exceeded, Na+ channels open (i.e., INa activates) and Na+ ions enter the cell down their electrochemical gradient. This results in displacement of the membrane potential toward the equilibrium potential for Na+ ions, around +50 mV. INa activation is transient, lasting at most 1 to 2 ms because, simultaneous with activation, a second, slightly slower conformational change in the channel molecule occurs (inactivation), which closes the ion pore in the face of continued membrane depolarization. The channel cannot open again until it has recovered from inactivation (i.e., regained its resting conformation), a process that requires repolarization to the resting potential for a defined period of time. The channels cycle through three states: resting (and available for activation), open, and inactivated. While the channel is inactivated, it is absolutely refractory to repeated stimulation.
Molecular Biology of Ion Channels
Ion Channel Pore and Selectivity Filter
The presence of four homologous domains in voltage-gated Na+ and Ca2+ channels suggests that basic ion channel architecture consists of a transmembrane pore surrounded by the four homologous domains arranged symmetrically (Fig. 5-1).