Capillary Endothelial Na+, K+, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology

• Published in: Headache Vol. 50; no. 3; pp. 459 - 478
• Main Authors: Harrington, Michael G., Fonteh, Alfred N., Arakaki, Xianghong, Cowan, Robert P., Ecke, Laurel E., Foster, Hailey, Hühmer, Andreas F., Biringer, Roger G.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.03.2010; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Animals; Biological and medical sciences; Brain - blood supply; Brain - metabolism; Brain - physiopathology; capillary endothelial cell (CEC); Cardiovascular system; Cerebral Arteries - metabolism; Cerebral Arteries - physiopathology; cerebrospinal fluid; Cerebrospinal Fluid - metabolism; Cortical Spreading Depression - physiology; Endothelial Cells - metabolism; Headaches; Homeostasis; Humans; K+ -ATPase transporter (NKAT); Medical sciences; Migraine; Migraine Disorders - cerebrospinal fluid; Migraine Disorders - metabolism; Migraine Disorders - physiopathology; Na+; Neurology; Pharmacology. Drug treatments; Potassium - analysis; Potassium - cerebrospinal fluid; Sodium - analysis; Sodium - cerebrospinal fluid; Sodium-Potassium-Exchanging ATPase - metabolism; Theory; Vascular diseases and vascular malformations of the nervous system; Vasodilator agents. Cerebral vasodilators; Headache; Endothelial cell; Nervous system diseases; Enzyme; Migraine; Adenosinetriphosphatase; Homeostasis; Cardiovascular disease; Cerebrospinal fluid; K; Cerebral disorder; Vascular disease; Pain; Na; ATPase transporter (NKAT); Central nervous system disease; Hydrolases; Neurological disorder; capillary endothelial cell (CEC); Cerebrovascular disease
• ISSN: 0017-8748; 1526-4610
• DOI: 10.1111/j.1526-4610.2009.01551.x

(Headache 2010;50:459‐478) Background.— Cerebrospinal fluid sodium concentration ([Na+]csf) increases during migraine, but the cause of the increase is not known. Objective.— Analyze biochemical pathways that influence [Na+]csf to identify mechanisms that are consistent with migraine. Method.— We reviewed sodium physiology and biochemistry publications for links to migraine and pain. Results.— Increased capillary endothelial cell (CEC) Na+, K+, ‐ATPase transporter (NKAT) activity is probably the primary cause of increased [Na+]csf. Physiological fluctuations of all NKAT regulators in blood, many known to be involved in migraine, are monitored by receptors on the luminal wall of brain CECs; signals are then transduced to their abluminal NKATs that alter brain extracellular sodium ([Na+]e) and potassium ([K+]e). Conclusions.— We propose a theoretical mechanism for aura and migraine when NKAT activity shifts outside normal limits: (1) CEC NKAT activity below a lower limit increases [K+]e, facilitates cortical spreading depression, and causes aura; (2) CEC NKAT activity above an upper limit elevates [Na+]e, increases neuronal excitability, and causes migraine; (3) migraine‐without‐aura may arise from CEC NKAT over‐activity without requiring a prior decrease in activity and its consequent spreading depression; (4) migraine triggers disturb, and treatments improve, CEC NKAT homeostasis; (5) CEC NKAT‐induced regulation of neural and vasomotor excitability coordinates vascular and neuronal activities, and includes occasional pathology from CEC NKAT‐induced apoptosis or cerebral infarction.