Jennifer Chen
Cluster 8
Malignant Hyperthermia
Abstract
A patient, waiting to undergo his cardiac surgery, is lying on a surgical platform. An
anesthesiologist enters the surgical room and injects some general anesthetics into the
patient’s bloodstream. The patient appears normal until after a few minutes, the patient
suddenly experiences increasing body temperatures leading to a high fever, muscle
rigidity, and increased heart rate. The anesthesiologist is perturbed, runs out of the
surgery room, and alerts the surgical staff of the patient’s alarming symptoms. The
surgical staff identifies the symptoms as Malignant Hyperthermia. What exactly is
Malignant Hyperthermia and how is it caused? Malignant Hyperthermia, a rare skeletal
muscular disease found in humans, pigs, horses, and many other animals, is a
channelopathy caused by abnormal calcium channels. This paper serves to investigate the
problems within the specific ion channels known to cause the disease. The goal of the
paper is to understand more about Malignant Hyperthermia and about how particular ion
channels associated with the disease operate. Learning about the chemistry behind the
disease is crucial in order to prevent future occurrences of Malignant Hyperthermia and
to design new treatments.
Introduction
Malignant hyperthermia is a fatal, inherited disorder that affects less than 200,000
people in the United States. [1] As mentioned in the abstract, Malignant Hyperthermia is
channelopathy, or a disease caused by mutations in channel protein genes. Malignant
Hyperthermia is triggered by anesthetics, which includes common inhalants, and by
medication containing succinylcholine, a substance often used as a muscle relaxant in
emergency medicines. [2] After the initial trigger, life-threatening symptoms ensue. These
symptoms include overly active metabolism in skeletal muscles, muscle contraction and
rigidness, rising body temperature, and difficulty removing carbon dioxide from the body.
[2]
Temperature can rise 1 C for every 5 minutes; hence, the word hyperthermia is
included in disease’s name. [3] If not treated immediately, death is a possible consequence.
Before we discuss the causes of
malignant hyperthermia, we must first
understand some background information about
calcium ion channels and the path the calcium
ions involved travel during muscle contraction.
For this process, refer to figure 1. First, an
action potential (nerve impulse) from a
sodium/potassium channel is triggered. [4] The
action potential reaches the T-tubule. [4]. The T
tubule (traverse tubule) is a deep fold of the cell
Figure 1 [9]
membrane that contains many L-type calcium
channels (also known as Dihydropyridine receptors). [6] L-type calcium channels are
voltage-gate channels that regulate the flow of Ca2+. [6] The action potential causes an
electrical difference near the L-type calcium channels and activates them. [3] As a result,
the L-type calcium channels open and allow Ca2+ ions to flow into the cell. Notice from
figure 1, there is a gap between the T tubule and the sarcoplasmic reticulum, a type of
smooth endoplastic reticulum organelle involved in pumping calcium ions and is a
storage room for the Ca2+ ions. [4]
How can Ca2+
ions cross this gap? Studies show that the L-type
calcium channel contains many subunits, as seen
in figure 2. One particular subunit, the α1, is very
close to the sarcoplasmic reticulum membrane at
various areas, known as triads, where there is only
Figure 2 [10]
a gap of approximately 120 A. [3] These triad regions contain “foot processes” that joins
the T tubule to the sarcoplasmic reticulum. [3] The foot processes are composed of 4 Ltype calcium channels (or
dihydropyridine receptors) paired
with 1 Ryanodine receptor
(RYR1). [3] (refer to figure 3 to
see the foot processes; only 2
dihydropyridine receptors instead
of 4 are shown for more clarity)
Figure 3 [3]
Through these foot processes, the
Ca2+ ions reaches the Ryanodine Receptor, causes the RYR1 to activate and release the
Ca2+ stored inside the sarcoplasmic reticulum. From there, the calcium ions continue to
proteins such as actin and myosin, which interact to ultimately allow muscle contraction.
Results
One cause of Malignant Hyperthermia has been linked to a mutation in the RYR1
gene. [3] The RYR1 is a ligand-gated calcium channel located in the membrane of the
sarcoplasmic reticulum. Ryanodine receptors, like other known ion channels, are gates,
controlling the movement of Ca2+ ions across the membrane. The ligand for RYR1 is
cytosolic (meaning inside the cell) Ca2+. [3] Scientists believe there are two binding sites
on the RYR1, one that is a “high-affinity site that induces channel opening and a lowaffinity site which inhibits the channel.” [3] The high-affinity site is know as the activation
site and the low-affinity site is known as the inhibit ion site. [4] The exact location of these
sites is undetermined. There are two sides to the ryanodine receptor: a cytoplasmic side
and a luminal side. (Refer to figure 4) The structure of RyR1 is similar to a clover with
four repeating parts. (Figure 4). [3]
Figure 4 [6]
provided by Terrence
Wagenknecht, from
Wadsworth Center, NY
State Dept. of Health
Scientists are able to study the disease through pigs, which have been found to
also have malignant hyperthermia. The disorder in pigs is called porcine stress syndrome
(PSS). [3] Because human research is difficult to undertake, many researchers are looking
at PSS pigs. Evidence from experiments show that PSS is a result of a mutation that
involves a substitution of arginine to cysteine at point 615 on the RYR1 gene. [3] In
humans, there are approximately 30 mutations, including the Arg615Cys substitution,
that can occur on the RYR1 gene. [5] However, how these mutations alter the ryanodine
channel is unknown.
We do know that the symptoms of the disease are due to excess levels of Ca2+
ions released from the sarcoplasmic reticulum inside skeletal muscle cells. [4] When a
person with Malignant Hyperthermia receives general anesthetics, a sudden and great
amount of Ca2+ ions is released. Ca2+ ions are involved in both metabolism ad muscle
contraction. [3] As a result, an overflow of Ca2+ ions would cause muscle contraction and
increased body metabolism. We now face a more difficult question: How do mutations in
the ryanodine channel cause it to release so much excess Ca2+?
From more recent studies, scientists have found that in PSS pigs, the “rate and
extent” [3] of Ca2+ released by ryanodine receptors is higher than compared to pigs that do
not have PSS. In addition, the channels open longer and close shorter, thus causing a
large amount Ca2+ ions being released. [3] In mutant RYR1, general anesthetics can
increase the affinity for cytosolic
Ca2+ to bind onto A- sites more,
while at the same time decrease
the affinity for cytosolic Ca2+ to
bind onto I- sites even more.
Figure 5
(Refer to figure 5) [4] Some
studies propose that cytosolic Mg2+ is a factor in the whole process. Cytosolic Mg2+ ions
are believed to be able to bind onto either the A-site or the I-site to inhibit the RYR1. [4]
By binding onto the A-site, the cytosolic Mg2+ blocks cytosolic Ca2+ ions from binding
onto the A-site. By binding onto the I-site, the cytosolic Mg2+ can inhibit the ryanodine
receptor directly. A mutated RYR1 channel seems to have lower attraction for the
cytosolic Mg2+. [4][7] Refer to figure 5 for an illustration of differences between affinities
of cytosolic Ca2+ cytosolic Mg2+ in normal and mutant RYR1. Therefore, there may
possibly be some sort of chemical structure change in the channel to cause such a reduced
attraction. As a result, the mutant RYR1 is less inhibited and more than normal amounts
of Ca2+ ions can be released. However, this explanation is contradictory because several
studies have shown that there is no decreased attraction with Mg2+ – that mutated RYR1
and normal RYR1 have similar affinities.
Another study proposed that Malignant Hyperthermia is a result of a process that
the researches called “store overload-induced Ca2+ release”. [8] This phrase basically
describes the process of when the sarcoplasmic reticulum contains an overload of Ca2+
ions, Ca2+ ions will be spontaneously released. [8] While previous studies mentioned
before focused on cytosolic Ca 2+ ions, this study focused on luminal Ca2+ ions. The
researchers discovered that in mutated Arg615Cys ryanodine receptors, the threshold
needed for luminal Ca2+ ions to activate the ryanodine receptor is lower. [8] The
activation of the ryanodine receptors leads to the “store overload-induced Ca2+ release”
process. [8] Therefore, in RYR mutated receptors, the “store overload-induced Ca2+
release” [8] process would be more likely to occur compared to normal RYR1. [8] The
study furthermore found that general anesthetic further reduced the threshold needed for
luminal Ca2+ ions to activate the ryanodine receptors even more. [8] Thus, the “store
overload-induced Ca2+ release” process is even more likely to occur and in turn, more
Ca2+ ions are released. [8]
Conclusion
Malignant Hyperthermia is a complicated disease that even today, scientists cannot
understand the complete molecular processes behind the ryanodine receptor. So far, we
know that the disease is caused by mutations in the RYR1 gene that cause the receptor to
release more than normal amounts of Ca2+ ions. However, we still face countless other
questions such as exactly how is the ryanodine receptor altered by such a mutation and
how do general anesthetics trigger the symptoms. Scientists must answer these pivotal
questions necessary for the understanding of the disease first. Once we have answered
these questions, we will have more hope of generating a better treatment or even cure for
Malignant Hyperthermia.
Acknowledgements
I would like to thank my chemistry professor, Toby Allen, for providing me the
inspiration to research about ion channels. I also thank chemistry professors Dean
Tantillo and Tim Patten for channeling your chemistry knowledge to me. I want to also
thank teacher fellow, Matt Peck, for providing advice and editing my paper. Also, I
would like to thank Clarabelle Cheng-Yue for proofreading my research paper.
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