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

BACKGROUND

Cerebrospinal fluid sodium concentration (Na(+)) increases during migraine, but the cause of the increase is not known.

OBJECTIVE

Analyze biochemical pathways that influence Na(+) 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(+). 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(+)) and potassium (K(+)).

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(+), facilitates cortical spreading depression, and causes aura; (2) CEC NKAT activity above an upper limit elevates Na(+), 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.