Conflict of Interest: None
Capillary Endothelial Na+, K+, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology
Version of Record online: 21 OCT 2009
© 2009 the Authors. Journal compilation © 2009 American Headache Society
Headache: The Journal of Head and Face Pain
Volume 50, Issue 3, pages 459–478, March 2010
How to Cite
Harrington, M. G., Fonteh, A. N., Arakaki, X., Cowan, R. P., Ecke, L. E., Foster, H., Hühmer, A. F. and Biringer, R. G. (2010), Capillary Endothelial Na+, K+, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology . Headache: The Journal of Head and Face Pain, 50: 459–478. doi: 10.1111/j.1526-4610.2009.01551.x
- Issue online: 1 MAR 2010
- Version of Record online: 21 OCT 2009
- Accepted for publication September 8, 2009.
- cerebrospinal fluid;
- K+ -ATPase transporter (NKAT);
- capillary endothelial cell (CEC)
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.