Gatekeeping: Penn Researchers Find
New Way to Open Ion Channels in Cell Membranes
Implications for Channel-Related Disorders, Drug Design
(Philadelphia, PA) - Using an enzyme found in the venom of the brown
recluse spider, researchers at the University of Pennsylvania
School of Medicine have discovered a new way to open molecular
pores, called ion channels, in the membrane of cells. The research team
- Zhe Lu, MD, PhD, Yajamana Ramu, PhD, and Yanping
Xu, MD, PhD of the Department of Physiology at Penn - screened
venoms from over 100 poisonous invertebrate species to make this discovery.
The enzyme, sphingomyelinase D (SMase D), splits a lipid called sphingomyelin
that surrounds the channel embedded in the cell membrane. As a result,
the channel opens to allow the passage of small ions into and out of the
cell, thereby generating electrical currents.
The new study, published online earlier this month in the journal Nature,
describes how SMase D opens one type of ion channel called a voltage-gated
potassium channel (from brain, but experimentally expressed in the membrane
of an oocyte, or egg cell) without changing the membrane voltage. The
finding introduces a new paradigm for understanding the gating of ion
channels and lays the conceptual groundwork for designing new drugs to
control ion-channel activity in medical intervention.
Voltage-gated ion channels are embedded in the cell membranes of most
types of cells. It has been known for over half a century that the channels
open and close in response to changes in electric voltage across the cell
membrane, hence their name. In some the cells, (commonly called “excitable”),
such as nerve, muscle, heart, and hormone-secreting cells, the channels
underlie electrical signaling. They selectively allow the passage of small
ions such as sodium, potassium, or calcium into and out of the cell. The
precisely controlled passage of ions generates the electrical currents
that enable nerve impulse transmission, hormone secretion, and muscle
contraction and relaxation. When there are changes to the channel, such
as by mutations in a channel gene, disease can result. For example, mutations
in some channel genes cause cardiac arrhythmias, including a form of the
lethal long QT syndrome.
Voltage-gated ion channels are also present in the so-called non-excitable
cells (such as immune, blood, and bone cells) whose membrane voltage stays
largely constant, as opposed to the excitable cells whose membrane voltage
constantly varies in a precisely controlled manner. How the activity of
channels in non-excitable cells is regulated has been a long-standing
biological mystery. This new finding that SMase D can open ion channels
without changing membrane voltage provides a clue to the mystery.
This work was supported by a research grant from the National Institutes
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