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A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels
- Source :
- Scientific Reports, Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
- Publication Year :
- 2017
- Publisher :
- Cold Spring Harbor Laboratory, 2017.
-
Abstract
- Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include both myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the ‘‘skeletal muscle’’ voltage-gated sodium channel, Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results indicate that, unlike in WT Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we also predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger myotonia or periodic paralysis in P1158S patients.SIGNIFICANCE STATEMENTVoltage-gated sodium channels (Nav) contribute to the physiology and pathophysiology of electrical signaling in excitable cells. Nav subtypes are expressed in a tissue-specific manner, thus they respond differently to physiological modulators. For instance, the cardiac subtype, Nav1.5, can be modified by changes in blood pH; however, the skeletal muscle subtype, Nav1.4, is mostly pH-insensitive. Nav1.4 mutants can mostly cause either hyper-or hypo-excitability in skeletal muscles, leading to conditions such as myotonia or periodic paralysis. P1158S uniquely causes both phenotypes. This study investigates pH-sensitivity in P1158S, and describes how physiological pH changes can push P1158S to cause myotonia and periodic paralysis.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Contraction (grammar)
Patch-Clamp Techniques
Nav1.4
Hypokalemic Periodic Paralysis
lcsh:Medicine
Action Potentials
Gating
CHO Cells
Voltage-Gated Sodium Channels
Article
Myotonia
03 medical and health sciences
0302 clinical medicine
Cricetulus
Hypokalemic periodic paralysis
Internal medicine
medicine
Animals
Humans
Amino Acid Sequence
lcsh:Science
Muscle, Skeletal
030304 developmental biology
Acidosis
0303 health sciences
Multidisciplinary
biology
Sequence Homology, Amino Acid
Chemistry
Sodium channel
lcsh:R
Skeletal muscle
Periodic paralysis
Hydrogen-Ion Concentration
medicine.disease
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Mutation
biology.protein
lcsh:Q
medicine.symptom
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Scientific Reports, Scientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
- Accession number :
- edsair.doi.dedup.....650ff3aa14a9f96aff502434e7e98e9d
- Full Text :
- https://doi.org/10.1101/164988