Table 2.—
Summary of Many of the Regulators of NKAT, Partitioned in Three Classes by Their Site of Modulation: Genetic, Direct, or Signal Transduction
| NKAT modulator | Site of modulation by class | Refs |
|---|---|---|
| Genetic class | ||
| FHM-1 | Gain of function in slow calcium channel. ↑ Ca2+ may modulate by dephosphorylating NKAT. | 72,125 |
| FHM-2 | Loss of function in α2 of NKAT. ↑ [Na+]i will alter NKAT expression. | 22 |
| FHM-3 | Gain of function in Na channel. ↑ [Na+]i will alter NKAT expression. | 25 |
| Dexamethasone | Increases NKAT via ↑RNA/protein. | 126 |
| Aldosterone | Increases NKAT via ↑RNA/protein. | 126 |
| TNFα | Down regulates NKAT via NF-κB. | 127 |
| Interleukin-1 | Increases NKAT localization and activity. | 128 |
| Thyroxine | Hyper- and hypothyroidism ↓ cerebellar NKAT. T3 ↑ muscle NKAT. | 129,130 |
| Direct class | ||
| Na/K | [Na+]i and [K+]e ↑NKAT by binding to a-chain. Inward Na currents can activate or inactivate NKAT. Resting membrane potential may modulate ion-binding. | 101,131–137 |
| Mg | Activates NKAT. Binds α-NKAT. Deprivation activates calcineurin-mediated Ca signaling. Dominant isolated renal Mg loss from γNKAT loss. | 101,138–141 |
| ATP and MgATP | Activates, binds α-NKAT. | 101 |
| V, Fe, Pb, Cu | Inhibits, binds NKAT. | 101 |
| Zn | Inhibits, binds NKAT. Involved in oxygen/glucose deprivation induced CSD. | 101,142 |
| Exogenous NKAT inhibitors | Specific inhibitors. Digoxin family. | 143–146 |
| Endogenous NKAT inhibitors | Specific endogenous inhibitors. Includes ouabain. | 147–153 |
| Phospholipids | Usually activate NKAT, but ↓ PE ↑ NKAT activity. | 103,154–156 |
| Cholesterol | ↓ NKAT. Lipid membrane fluidity and binds receptor. | 157,158 |
| Kinases | Generally inhibit NKAT, eg, PKA/PKC/PKG phosphorylation. | 159,160 |
| Phosphatases | Generally activate NKAT. | 159 |
| Signal transduction class | ||
| Ca | α1/2 NKAT interacts with NCX to regulate Ca2+. Release of membrane-bound intracellular Ca2+ ↑ NKAT by activating calcineurin-mediated dephosphorylation. Physiological Ca2+ levels do not change α-1, but inhibit α-2 and 3 NKAT. | 100,107,161 |
| Dopamine | D1-mediated (D1&5 receptors) via G protein, PKA, and adenyl cyclase, ↑NKAT. D2-mediated (D2,3,4 receptors) inhibits G proteins, via PKC, decreasing adenyl cyclase and ↓ α2 and 3 NKAT. | 162–164 |
| Norepinephrine | Activates NKAT via α1 adrenoreceptor, ↑Ca, activating calcineurin and dephosphorylating NKAT. Beta adrenergic receptors ↓ NKAT via cAMP-mediated inhibition of phosphatase PP1. | 157,165–168 |
| Serotonin | Agonists ↑the # of NKATs, antagonists inactivate NKAT. Activate 5HT1A in cortex, 5HT6 in cerebellum. Inactivate NKAT in choroid via 5HT2c, DAG and PKC-induced phosphorylation. Activates glial α2 NKAT. | 160,169,170 |
| Prostanoids, leukotrienes, and thromboxanes | Through GPCRs, G proteins, camp, and phosphorylation. Also prostaglandin responsive elements in NKAT transcription. | 171–173 |
| Nitric oxide | NO donors trigger migraine via cGMP, and blockade of NOS treats migraine with aura. | 174 |
| Estrogen | Activate 5HT2AR and SERT, may activate NKAT. | 175,176 |
| Glutamate | Activate NKAT via increased [Na+]i by ↑Na influx, and by G protein and PKG. | 101,177–179 |
| Cannabinoids | Activate NKAT via CB1 receptors via G proteins. Anandamide NKAT, possibly by inhibiting dopamine and 5HT uptake. | 180,181 |
| Hypoxia | Acutely degrades NKAT. 24 hours after hypoxia, ↑ α1 and 2 NKAT activity, via PKMζ. GM1 protects after ischemia. | 142,159,182,183 |
| CO | Induces persistent NKAT activation in Purkinje neurons, via G proteins and PKG. | 179 |
| Lipid peroxidation | MMA inhibits succinate dehydrogenase, increases TBARS, depresses NKAT in some locations, increases in others. 4HNE ↓ Dopamine uptake and NKAT activity. | 179,184–187 |
| Insulin | Increases α1 NKAT in cultured astrocytes via IGF-1R. | 126,188,189 |
| Endothelin | ↑NKAT in ciliary cells/brain capillary endothelium. | 190–192 |
| CGRP | Increases NKAT in depolarized (high [K+]e) muscle. | 193,194 |
| Capsaicin | Capsaicin releases CGRP at sensory nerve endings. Capsazepine inactivates NKAT, inhibits ATP hydrolysis. | 194,195 |
| Caffeine | Inhibits NKAT via GPCRs Adenosine A1a, A2a, A2b. | 196 |
CGRP = calcitonin G related peptide; CSD = cortical spreading depression; FHM = familial hemiplegic migraine; IGF-1 = insulin growth factor 1; NKAT = Na+, K+ -ATPase transporter.