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  • HYPERKALEMIC PERIODIC PARALYSISDanielle Swadberg, Brock Roberts, Sameen Singh, Chelle Wheat

  • Twenty years ago, a quarterhorse named Impressive won all of the titles of his class. He was the top-winning, top-producing Quarter Horse stallion of all time.

    As a breeding stallion, he proved himself equally deserving of his name, turning out champion after champion. Many of Impressive's offspring bore the same dramatic physical stature as their sire - they too went on to become outstanding and prolific stallions and broodmares. Of the top 15 halter horses in 1992, 13 were descendants of Impressive. Even at the age of 23, Impressive himself was fourth on the list. In 1993, it was estimated that more than 55,000 Quarter Horses, Paints, and Appaloosas bore his pedigree.

    From the American Quarterhorse Association

  • Soon his progeny were seen to be affected by a strange muscular twitching that often left them temporarily unable to move.

    Usually mis-diagnosed as tying-up syndrom or colic, these episodes varied widely in degree and duration....but all had one factor in common, their pedigree. As a result, many people now know HYPP by its more common name: Impressive Syndrome.

    This turned out to be a genetic mutation that only recently has been implicated in the rare but burgeoning - and sometimes fatal - muscular disorder known as hyperkalemic periodic paralysis.

    This particular defect is a dominant condition, meaning that at least half of the affected horses' offspring will be affected as well. In the words of one prominent Quarter Horse trainer, this discovery was "one of the most devastating things that ever hit the horse industry."

  • Hyperkalemic Period Paralysis or HYPP in horses is characterized by sporadic attacks of muscle tremors, weakness and collapsing. These HYPP attacks can also involve loud breathing noises from paralysis of the muscles of the upper airway. Sudden death can occur in these horses from heart failure or respiratory muscle paralysis. Using electromyography (EMG) to measure the electrical activity present in certain muscles, the researchers discovered a wide variety of abnormalities, including spontaneous activity from muscles under no stimulation. Because these muscle tremors happen in other diseases besides HYPP, those results were not enough evidence to give an accurate diagnosis. Eventually, a mutation in a Na channel of the skeletal muscles was found, which was the official diagnosis of HYPP.

  • The disorder involves attacks of muscle weakness or paralysis, alternating with periods of normal muscle function. Attacks usually begin in early childhood. Multiple daily attacks are not uncommon. Attacks typically last only 1 to 2 hours, but can sometimes last as long as a day. They tend to occur while resting after exercise or exertion.

    Risks include a family history of periodic paralysis. Attacks may be triggered by fasting. Attacks seldom occur during exercise but may be triggered by rest following exercise. Disorders that cause intermittent episodes of paralysis as their primary effect are uncommon. More commonly, an intermittent episode of paralysis or weakness is a symptom of another disorder. Hyperkalemic periodic paralysis occurs in approximately 1 in every 100,000 people. Men are affected more often than women and usually have more severe symptoms.

    Humans also can have HPP (HyperKPP)

  • Weakness/paralysisMost commonly located in the shoulders and hips Arms and legs may also be involved Occurs intermittently May occur on awakening May be triggered by rest after exerciseMay be triggered by fasting Usually lasts for less than 2 hoursSpontaneous recovery of normal strength between attacks Normal alertness during attacks

    Human Symptoms

  • The human defect is also in Na channels

  • The human defect is also in Na channels

  • Treatment is to temporarily increase blood glucose or calcium, or to use K-specific diuretics

  • Voltage Gated Na+ channelsMuscles are excitable cells

  • The ProteinLLinker between domains III and IVSS4-S5 LinkerSS6 segmentPurpose of this Study:EElucidate the Molecular Biology of HyperKPPcsbn.concordia.ca/psyc358/ Lectures/voltgate.htm

  • Functional Processes of the Protein ActivationThis refers to the proteins ability to open its activation gate (m gate) in response to depolarizing changes in membrane potentialThis initiates the action potential when the threshold potential is reachedStudies revolve around quantifying the potential where this response occurs

  • Functional Processes of the ProteinFast InactivationThis is the ability of the protein to close its inactivation gate (h gate) in response to depolarizing changes in membrane potentialOccurs with a slight delay, so that activation and fast inactivation work in tandem to produce action potentials with short durationStudies are aimed at quantifying the degree of depolarization required to close the h gate

  • Activation & Fast Inactivation csbn.concordia.ca/psyc358/ Lectures/Nachannel.htm

  • Functional Processes of the ProteinSlow InactivationRefers to the proteins tendency to inactivate after extended depolarizationInvolves unknown molecular mechanismThe potential required to inactivate, as well as the time required to recover from inactivation, are quantifiable and of interest to researchers

  • Activation25 msec20 mV10 mV 0 mV-10 mV-20 mV-30 mV-40 mV-50 mV-60 mV-70 mV-80 mV-120 mV-Depolarize to different potentials from a fixed holding potential-Each depolarization results in a quantified current-Current converted to conductance values and normalized-Determines activation of channel as function of potential

  • ActivationIn molecular terms, this protocol is designed to establish the potential that is required to open the activation gateIn effect, this determines the threshold potential for this ion channel

  • Fast Inactivation-50 mV -60 mV-70 mV-80 mV-90 mV-100 mV-110 mV-120 mV-40 mV-30 mV-20 mV-10 mV0 mV200 msec10 mV20 mV25 msec-Depolarize to fixed potentials from varied holding potentials-Each depolarization results in a quantified current-Current normalized as a fraction of peak current-Determines current as a function of holding potential0 mV

  • Fast InactivationThis protocol is designed to determine the degree of depolarization required to close the inactivation gateIf the holding potential is sufficiently depolarized, the inactivation gate is closed Subsequent depolarization to a potential where the activation gate is open generates no current. Why? Answer: Inactivation gate is already closed

  • Slow Inactivation50 sec10 mV-50 mV-70 mV-80 mV-90 mV-40 mV-30 mV-20 mV-10 mV0 mV-60 mV-100 mV-110 mV-120 mV30 msec20 msec-Holding potential is varied, then hyperpolarized to a fixed potential, then depolarized to a fixed test potential-Varied potential is held for a much longer period of time than other protocols, and all membrane changes are sequential

  • Slow Inactivation50 sec-130 mV-100 mV30 msec20 msec-10 mV30 msec20 msec-10 mV50 secChange in holding potential-Emphasis on Sequential Potential ChangesCurrent measured-100 mV

  • Slow InactivationThis protocol is designed to determine the degree of depolarization necessary to invoke slow inactivationAssumption: brief hyperpolarizations designed to remove the effect of fast inactivation have a negligible effect on slow inactivation

  • Slow Inactivation Recovery-20 mV>15 min-100 mV50 sec50 sec-Part one: fast recoveryIncreasing recovery time duration50 sec-10mV, 20 msec, current measured -100 mV-100 mV-100 mVRemoves fast inactivation, allows recovery

  • Slow Inactivation Recovery

    -20 mV-100 mVPart two: continuous slow recovery 50 sec0.5 sec5 sec15 sec-10mV, 20 msec, current measured

  • Slow Inactivation RecoveryThe slow inactivation recovery protocol monitors the amount of time at hyperpolarized potentials required for the slow inactivation gate to open after extended depolarization closes itThis is determined by monitoring the current elicited by rapid depolarization as a function of the amount of recovery time at hyperpolarized potentials

  • RESULTS

    Six different tests were conducted:

    ActivationFast inactivationSlow InactivationSlow Inactivation RecoveryDeactivationPersistent Current

  • ACTIVATION & FAST-INACTIVATION Results:

    Slight hyperpolarizing shift in activation curve

    No accountable change in fast inactivationFast-inactivationActivationNeurology 2002;58:p.1270

  • T704 MUTATIONFast-inactivationActivationCannon, S.C. NeuromuscularDisorders, 1997 p.244

  • SLOW INACTIVATION Results:

    Slow inactivation doesnot occur as easily in the mutated channel Neurology 2002;58:p.1271

  • SLOW INACTIVATION RECOVERY Results:

    Slow inactivation recovery is easier in the mutated channel than the wild-typeNeurology 2002;58:p.1271

  • DEACTIVATION Results:

    Deactivation was samefor mutated channeland the wild-type channelNeurology 2002;58:p.1270

  • PERSISTENT CURRENT Results:

    L689I mutation showed a slight current after 50msWild-type showed no persistent currentNeurology 2002;58:p.1269

  • SUMMARY OF RESULTS Test Results Conclusion

    1) ActivationSlight hyperpolarizing shift in activation curveMutated channel can open at slightly lower membrane potentials2) Fast InactivationNot affectedNo accountable difference3) Slow InactivationLess mutated channels slow inactivated compared to wild-type Mutated channel does inactivate a