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.

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This work was supported by a research grant from the National Institutes of Health.

This release can also be seen at: www.uphs.upenn.edu/news.

PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.


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