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Solution structure of the NaV1.2 C-terminal EF-hand domain. 2009

Vesselin Z Miloushev, and Joshua A Levine, and Mark A Arbing, and John F Hunt, and Geoffrey S Pitt, and Arthur G Palmer
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032-3702, USA.

Voltage-gated sodium channels initiate the rapid upstroke of action potentials in many excitable tissues. Mutations within intracellular C-terminal sequences of specific channels underlie a diverse set of channelopathies, including cardiac arrhythmias and epilepsy syndromes. The three-dimensional structure of the C-terminal residues 1777-1882 of the human NaV1.2 voltage-gated sodium channel has been determined in solution by NMR spectroscopy at pH 7.4 and 290.5 K. The ordered structure extends from residues Leu-1790 to Glu-1868 and is composed of four alpha-helices separated by two short anti-parallel beta-strands; a less well defined helical region extends from residue Ser-1869 to Arg-1882, and a disordered N-terminal region encompasses residues 1777-1789. Although the structure has the overall architecture of a paired EF-hand domain, the NaV1.2 C-terminal domain does not bind Ca2+ through the canonical EF-hand loops, as evidenced by monitoring 1H,15N chemical shifts during aCa2+ titration. Backbone chemical shift resonance assignments and Ca2+ titration also were performed for the NaV1.5 (1773-1878) isoform, demonstrating similar secondary structure architecture and the absence of Ca2+ binding by the EF-hand loops. Clinically significant mutations identified in the C-terminal region of NaV1 sodium channels cluster in the helix I-IV interface and the helix II-III interhelical segment or in helices III and IV of the NaV1.2 (1777-1882) structure.

UI MeSH Term Description Entries
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D009419 Nerve Tissue Proteins Proteins, Nerve Tissue,Tissue Proteins, Nerve
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D004827 Epilepsy A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313) Aura,Awakening Epilepsy,Seizure Disorder,Epilepsy, Cryptogenic,Auras,Cryptogenic Epilepsies,Cryptogenic Epilepsy,Epilepsies,Epilepsies, Cryptogenic,Epilepsy, Awakening,Seizure Disorders
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000200 Action Potentials Abrupt changes in the membrane potential that sweep along the CELL MEMBRANE of excitable cells in response to excitation stimuli. Spike Potentials,Nerve Impulses,Action Potential,Impulse, Nerve,Impulses, Nerve,Nerve Impulse,Potential, Action,Potential, Spike,Potentials, Action,Potentials, Spike,Spike Potential
D001145 Arrhythmias, Cardiac Any disturbances of the normal rhythmic beating of the heart or MYOCARDIAL CONTRACTION. Cardiac arrhythmias can be classified by the abnormalities in HEART RATE, disorders of electrical impulse generation, or impulse conduction. Arrhythmia,Arrythmia,Cardiac Arrhythmia,Cardiac Arrhythmias,Cardiac Dysrhythmia,Arrhythmia, Cardiac,Dysrhythmia, Cardiac
D013577 Syndrome A characteristic symptom complex. Symptom Cluster,Cluster, Symptom,Clusters, Symptom,Symptom Clusters,Syndromes
D015222 Sodium Channels Ion channels that specifically allow the passage of SODIUM ions. A variety of specific sodium channel subtypes are involved in serving specialized functions such as neuronal signaling, CARDIAC MUSCLE contraction, and KIDNEY function. Ion Channels, Sodium,Ion Channel, Sodium,Sodium Channel,Sodium Ion Channels,Channel, Sodium,Channel, Sodium Ion,Channels, Sodium,Channels, Sodium Ion,Sodium Ion Channel

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