(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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