Editorial-Channelopathies: a link between brain and heart: the model of epilepsy

P Iannetti, G Farello, A Verrotti, Alberto Verrotti
2017 European Review for Medical and Pharmacological Sciences   unpublished
Channelopathies are a various set of disorders characterized by the dysfunction of ion channels in the membranes of all cells and many cellular organelles. Many pediatric diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis) can be caused by channelopathies. Moreover, also diseases of the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada
more » ... drome, and catecholaminergic polymorphic ventricular tachycardia), of the respiratory system (e.g., cystic fibrosis), of the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperal-dosteronism), of the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, auto-somal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and of the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaacs' syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis) can be a consequence of a malfunction of the ion channel 1. Transient Receptor Potential (TRP) channel proteins are another family of proteins that are expressed in many tissues and cell types. TRP channels respond to different stimuli, including light, mechanical or chemical stimuli, temperature, pH or osmolarity 2. Recent studies showed that TRP channel dysfunction significantly contributes to the pathophysiology of cardio-vascular, neurological, metabolic or neoplastic disorders 3. Ion channels play a pivotal role in generating membrane potential and function in several cellular activities, such as signal transduction, neurotransmitter release, muscle contraction, hormone secretion, hydro electrolyte balance, growth, motility, and apoptosis. Ion channels are classified according to the types of ions passing through them, the factors of their gating, their tissue expression patterns, and their structural characteristics. Ion channels can be in one of the following states: open, inactivated closed (refractory period), and resting closed. The gating (opening and closing) of ion channels is controlled by membrane potential (voltage), ligands (e.g., hormones and neurotransmitters), second messengers (e.g., calcium and cyclic nucleotides), light, temperature, and mechanical changes. Ion channels can be formed from a single protein (e.g., cystic fibrosis transmembrane conductance regulator, a chloride channel). Otherwise, ion channels can be formed from an assembly of several subunits, each a protein encoded by a different gene. More than 600 ion channel genes have been identified. Congenital cardiac and cerebral channelopathies are the consequence of mutations in different genes encoding for sodium (Na), potassium (K) and calcium (Ca) voltage-gated channels. In principle , Na-channels are involved in cardiac channelopathies, whilst K+ and Ca+ channels appear to be responsible for seizures and other neuromuscular disorders. Nevertheless, the increasing reports of patients/families presenting with epilepsy and cardiac arrhythmias and a unique mutation in one of the channel genes suggest a strict correlation between the two phenotypes. Cardiac action potentials are generated from a delicate balance of several ionic currents. When there is a derangement in the function of the ion channel, life-threatening cardiac arrhythmias may occur when this equilibrium is impaired by ion channel derangement. Cardiac channelopathies are responsible for about half the sudden arrhythmic death syndrome cases and, at least, one out of five sudden infant death syndrome cases. Mutations in calcium, sodium, potassium, and TRP channel