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

Authors

  • Michael G. Harrington MB, ChB, FRCP,

    1. From the Huntington Medical Research Institutes, Pasadena, CA, USA (M.G. Harrington, A.N. Fonteh, X. Arakaki, R.P. Cowan, L.E. Ecke, and H. Foster); Thermo Fisher Scientific, San Jose, CA, USA (A.F. Hühmer, and R.G. Biringer); University of Pennsylvania, Philadelphia, PA, USA (L.E. Ecke).
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  • Alfred N. Fonteh PhD,

    1. From the Huntington Medical Research Institutes, Pasadena, CA, USA (M.G. Harrington, A.N. Fonteh, X. Arakaki, R.P. Cowan, L.E. Ecke, and H. Foster); Thermo Fisher Scientific, San Jose, CA, USA (A.F. Hühmer, and R.G. Biringer); University of Pennsylvania, Philadelphia, PA, USA (L.E. Ecke).
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  • Xianghong Arakaki MD, PhD,

    1. From the Huntington Medical Research Institutes, Pasadena, CA, USA (M.G. Harrington, A.N. Fonteh, X. Arakaki, R.P. Cowan, L.E. Ecke, and H. Foster); Thermo Fisher Scientific, San Jose, CA, USA (A.F. Hühmer, and R.G. Biringer); University of Pennsylvania, Philadelphia, PA, USA (L.E. Ecke).
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  • Robert P. Cowan MD,

    1. From the Huntington Medical Research Institutes, Pasadena, CA, USA (M.G. Harrington, A.N. Fonteh, X. Arakaki, R.P. Cowan, L.E. Ecke, and H. Foster); Thermo Fisher Scientific, San Jose, CA, USA (A.F. Hühmer, and R.G. Biringer); University of Pennsylvania, Philadelphia, PA, USA (L.E. Ecke).
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  • Laurel E. Ecke BS,

    1. From the Huntington Medical Research Institutes, Pasadena, CA, USA (M.G. Harrington, A.N. Fonteh, X. Arakaki, R.P. Cowan, L.E. Ecke, and H. Foster); Thermo Fisher Scientific, San Jose, CA, USA (A.F. Hühmer, and R.G. Biringer); University of Pennsylvania, Philadelphia, PA, USA (L.E. Ecke).
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  • Hailey Foster BA,

    1. From the Huntington Medical Research Institutes, Pasadena, CA, USA (M.G. Harrington, A.N. Fonteh, X. Arakaki, R.P. Cowan, L.E. Ecke, and H. Foster); Thermo Fisher Scientific, San Jose, CA, USA (A.F. Hühmer, and R.G. Biringer); University of Pennsylvania, Philadelphia, PA, USA (L.E. Ecke).
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  • Andreas F. Hühmer PhD,

    1. From the Huntington Medical Research Institutes, Pasadena, CA, USA (M.G. Harrington, A.N. Fonteh, X. Arakaki, R.P. Cowan, L.E. Ecke, and H. Foster); Thermo Fisher Scientific, San Jose, CA, USA (A.F. Hühmer, and R.G. Biringer); University of Pennsylvania, Philadelphia, PA, USA (L.E. Ecke).
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  • Roger G. Biringer PhD

    1. From the Huntington Medical Research Institutes, Pasadena, CA, USA (M.G. Harrington, A.N. Fonteh, X. Arakaki, R.P. Cowan, L.E. Ecke, and H. Foster); Thermo Fisher Scientific, San Jose, CA, USA (A.F. Hühmer, and R.G. Biringer); University of Pennsylvania, Philadelphia, PA, USA (L.E. Ecke).
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  • Conflict of Interest: None

M.G. Harrington, HMRI – Molecular Neurology, 99 North El Molino Avenue, Pasadena, CA 91101, USA.

Abstract

(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.

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