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J Biol Chem. 2019 Jun 18. pii: jbc.RA118.006248. doi: 10.1074/jbc.RA118.006248. [Epub ahead of print]

Peripheral myelin protein 22 modulates store operated calcium channel activity, providing insights into Charcot-Marie-Tooth disease etiology.

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Vanderbilt University School of Medicine, United States.
Department of Biochemistry, Vanderbilt University School of Medicine, United States.


Charcot-Marie-Tooth (CMT) disease is a peripheral neuropathy associated with gene duplication and point mutations in the peripheral myelin protein 22 (PMP22) gene. However, the role of PMP22 in Schwann cell physiology and the mechanisms by which PMP22 mutations cause CMT are not well understood. On the basis of homology between PMP22 and proteins associated with modulation of ion channels, we hypothesized that PMP22 alters ion channel activity. Using whole-cell electrophysiology we show here that heterologous PMP22 expression increases the amplitude of currents similar to those ascribed to store- operated calcium (SOC) channels, particularly those involving transient receptor canonical channel 1 (TrpC1). These channels help replenish Ca+2 in the endoplasmic reticulum (ER) following stimulus-induced depletion. Currents with similar properties were recorded in wild type but not pmp22-/- mouse Schwann cells. Heterologous expression of the CMT-associated PMP22_L16P variant, which fails to reach the plasma membrane and localizes to the ER, led to larger currents than wild type PMP22. Similarly, Schwann cells isolated from Trembler J (TrJ; PMP22_L16P) mice had larger currents than wild type littermates. Calcium imaging in live nerves and cultured Schwann cells revealed elevated intracellular Ca+2 in TrJ mice compared with wild type. Moreover, we found that PMP22 co-immunoprecipitated with stromal interaction molecule 1 (STIM1), the Ca+2 sensor SOC channel subunit in the ER. These results suggest that in the ER, PMP22 interacts with STIM1 and increases Ca+2 influx through SOC channels. Excess or mutant PMP22 in the ER may elevate intracellular Ca+2 levels, which could contribute to CMT pathology.


Charcot-Marie-Tooth disease (CMT); PMP22_L16P; Schwann cells; calcium release-activated calcium channel protein 1 (ORAI1); endoplasmic reticulum stress (ER stress); gas3; myelin protein; myelination; neuropathy; stromal interaction molecule 1 (STIM1); transient receptor potential channels (TRP channels)

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