Luis Fernando Santana
University of Maryland (Baltimore), 1996
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CA2+ SIGNALING IN CARDIAC AND VASCULAR SMOOTH MUSCLE
Research in our laboratory focuses on cardiac and vascular smooth muscle. We are particularly interested in determining how cell-wide (or global) and local changes in Ca2+ modulate the function of these cells. To investigate this we combine a series of state-of-the-art techniques including patch-clamp electrophysiology, molecular biology, cell biology, confocal and two-photon microscopy.
There are two ongoing projects in the laboratory. The goal of one of our projects is to investigate the molecular mechanisms underlying arrhythmias during heart failure (HF). Arrhythmias are the major cause of death during heart failure, yet their molecular causes are incompletely understood. Recent reports suggest that an increase in the duration of the action potential (AP) of cardiac myocytes is the major arrhythmogenic event during HF. Interestingly, this prolongation of the AP of failing cardiac myocytes occurs in the absence of known genetic changes that affect membrane currents. Recent work in the lab suggests that post-translational glycosylation of Na+ and K+ channel proteins is altered during HF. Deficient de-glycosylation alter the currents produced by Na+ and K+ channels in ways that increase AP duration and arrhythmogenesis. Current experiments examine the cellular and molecular changes in cardiac cells leading to defective glycosylation of ion channels during HF.
The other project that our laboratory is working on focuses on the mechanisms controlling the diameter of cerebral arteries, which controls blood flow to the brain. The contractile state of vascular smooth muscle cells is ultimately responsible for the regulation of arterial diameter. It has been well established that increases in intravascular pressure constrict cerebral arteries via membrane depolarization of vascular smooth muscle cells, which increases the steady-state open probability of Ca2+ channels. The opening of Ca2+ channels, in turn, increases Ca2+ influx and causes a or global increase in [Ca2+]i that causes arterial constriction. Ca2+ channels have been traditionally thought to control [Ca2+]i by supplying Ca2+ directly to the cytosol and by stimulating Ca2+ release through ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR). However, we showed that localized Ca2+ release events through RyRs, called "Ca2+ sparks" acting as a negative feedback element, stimulate nearby Ca2+-activated potassium (KCa) channels to cause membrane potential hyperpolarization and thus a reduction in activity of Ca2+ channel activity which causes a reduction in global [Ca2+]i and relaxes vascular smooth muscle cells. These results suggested that the strength and efficacy of Ca2+ signals from Ca2+ channels to RyRs and KCa channels, as well as from RyRs to Ca2+ channels and KCa channels depends on the relative location of these proteins, their sensitivity to Ca2+, and the frequency and amplitude of the local Ca2+ signals. We recently found that these Ca2+ signals are profoundly altered by vasodilators that elevate cAMP (i.e. forskolin) and cGMP (e.g. nitric oxide). Current experiments are aimed at examining, at the molecular level, the mechanism by which these vasodilators modulate the communication among KCa, RyRs and Ca2+ channels via Ca2+ signals.