Voltage-Gated Sodium Channels Dysfunction in Depression: The Hypothesis

Voltaj bağımlı sodyum kanalları nöronlarda sinyal iletimi, kas kontraksiyonu, hormon salınımı, kardiyak pacemaker ve nörotransmitter salınımı gibi birçok fizyolojik süreçte aksiyon potansiyelinin oluşumunda rol oynar. Trisiklik antidepresanlar ve duloksetin gibi bazı antidepresanlar voltaj bağımlı sodyum kanallarını etkileyebilir. Kanalopatiler olarak da bilinen sodyum kanalı gen mutasyonları epilepsi, kronik ağrı, migren ve kardiyak aritmiler gibi bazı kalıtsal hastalıklara yol açabilir. Bu hastalıkların birçoğu depresyona benzer şekilde epizodik, ataklarla seyreden, ataklar arasında normal veya normale yakın bir işlevselliğe dönen, psikolojik stres faktörleriyle artış gösteren özelliklere sahiptir. Sodyum kanal gen mutasyonlarının ayrıca intihar girişimlerine yatkınlık, uyku bozukluğu, hipotalamo-hipofizer adrenal eksen disfonksiyonunu gösteren kortikosteroidlerin salınımının diurnal ritminde bozulma ile ilişkili olduğu gösterilmiştir. Voltaj bağımlı sodyum kanallarının nöromodulasyonu depresyonun patofizyolojine de katkıda bulunan cAMP-bağımlı protein kinaz A ve protein kinaz C aracılı nöroplastisite ve hücresel yenilenmede (resilience) önemli rol oynar. Antidepresan ilaçlar ve somatik tedaviler (örneğin; elektrokonvülsif terapi ve transkraniyal manyetik stimulasyon) hücresel direnci arttıran CREB (cAMP response element binding protein) ve BDNF (brain derived neurotrophic factor) gibi birçok nörotropinleri düzenler. Bu bulgular depresyonda voltaja bağımlı sodyum kanallarının disfonksiyonu hipotezini desteklemektedir.

Depresyonda voltaja bağımlı sodyum kanallarının disfonksiyonu: Bir hipotez

Voltage-gated sodium (Na+) channels (VGSCs) are responsible for action potential initiation and propagation in most electrically excitable cells which are implicated in a wide range physiological functions including neuronal signalling, muscle contraction, endocrine secretion, cardiac pacemaking, as well as neurotransmitter releases. VGSCs are targets for certain antidepressant drugs such as tricyclic antidepressant and duloxetine. Sodium channel gene mutations are associated with a variety of inherited diseases known as channelopathies such as epilepsy, chronic pain, migraine and cardiac arrhythmia. A common clinical features of many channelopathies are the paroxysmal symptoms, discrete attacks, usually precipitated by a physiologic stress, and most people return to normal or near normal function between attacks similar to depression. It has been demonstrated that sodium channel gene mutations are also associated with increased susceptibility to suicidal attempts, sleep disturbance, dysregulation of diurnal rhythm in corticosterone secretion indicating hypothalamicpituitary-adrenal axis dysfunction. Neuromodulation of voltage-gated sodium channels plays an important role in regulating neuroplasticity and cellular resilience mediated by cAMP-dependent PKA and PKC that could contribute to pathophysiology of depression. Antidepressant drugs and somatic therapies (e.g., electroconvulsive therapy, and transcranial magnetic stimulation) regulate a number of neurotrophins such as cAMP response element binding protein and brain derived neurotrophic factor which have the potential to increase neuroplasticity and cellular resilience. These findings support the hypothesis that sodium channel dysfunction may be involved in the etiology of depression.

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