Capillary endothelial Na(+), K(+), ATPase transporter homeostasis and a new theory for migraine pathophysiology.
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.


METHODS
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.
Harrington
Michael G
MG
Huntington Medical Research Institutes - Molecular Neurology, Pasadena, CA 91101, USA.
Fonteh
Alfred N
AN
Arakaki
Xianghong
X
Cowan
Robert P
RP
Ecke
Laurel E
LE
Foster
Hailey
H
Hühmer
Andreas F
AF
Biringer
Roger G
RG
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D002536:Cerebral Arteries / Q000378:metabolism* / Q000503:physiopathology*; D002555:Cerebrospinal Fluid / Q000378:metabolism; D013181:Cortical Spreading Depression / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008881:Migraine Disorders / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000503:physiopathology*; D011188:Potassium / Q000032:analysis / Q000134:cerebrospinal fluid; D012964:Sodium / Q000032:analysis / Q000134:cerebrospinal fluid; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium