Endogenous regulation and de novo-pharmacology modulation of the sodium leak channel complex

The sodium leak channel (NALCN) is the ion-conducting subunit of the NALCN complex.

NALCN sets the resting membrane potential (RMP) in excitable tissue (e.g. brain and uterine wall), controlling neuronal activity and muscle contraction.

The NALCN complex is essential for survival and both loss- or gain of function mutations in the complex cause severe developmental disorders (CLIFAHDD and IHPRF). Yet, NALCN physiology is largely unknown and no selective or specific compounds targeting NALCN exist.

In this proposal, I aim to I) characterize regulation of the NALCN complex by endogenous protein partner interactions, and II) identify and classify de novo designer proteins that potentiate or inhibit NALCN.

I anticipate that this can inform on NALCN physiology, and future therapeutic strategies to counteract NALCN loss- or gain of function. I will perform Aim I-II in the lab of Stephan Pless at Copenhagen University during year 1-2. Promising preliminary data were obtained in silico with some experimental validation.

Here, I will elucidate the aims experimentally.

I will utilize – and expand – my experience in ion-channel regulation, electrophysiological- and immunocytochemistry techniques.

With the expertise gained in year 1-2, I will in year 3 collect preliminary data for a new line of research under the guidance of Sara Liin at Linköping University. I will investigate NALCN channelosome regulation by hormones, important for uterine wall contractility.