Jentsch, T. J. | Search bioRxiv

bioRxiv2023

KCNQ5 controls perivascular adipose tissue-mediated vasodilation

BackgroundSmall arteries exhibit resting tone, a partially contracted state that maintains arterial blood pressure. In arterial smooth muscle cells (SMCs), potassium channels control contraction and relaxation. Perivascular adipose tissue (PVAT) has been shown to exert anticontractile effects on the blood vessels. However, the mechanisms by which PVAT signals small arteries, and their relevance, remain largely unknown. We aimed to uncover key molecular components in adipose-vascular coupling. MethodsA wide-spectrum of genetic mouse models targeting Kcnq3, Kcnq4 and Kcnq5 genes (Kcnq3-/-, Kcnq4-/-, Kcnq5-/-, Kcnq5dn/dn, Kcnq4-/-/Kcnq5dn/dn, Kcnq4-/-/Kcnq5-/-), telemetry blood pressure measurements, targeted lipidomics, and RNA-Seq profiling, wire-myography, patch-clamp, and sharp-electrode membrane potential measurements were used. ResultsWe show that PVAT causes SMC KCNQ5 (KV7.5) channels to hyperpolarize the membrane potential. This effect relaxes small arteries and regulates blood pressure. Oxygenation of polyunsaturated fats generates oxylipins, a superclass of lipid mediators. We identified numerous oxylipins released by PVAT that potentiate vasodilatory action in small arteries by opening SMC KCNQ5 channels. ConclusionsOur results reveal a key molecular function of KCNQ5 channels in adipose-vascular coupling, translating PVAT signals, particularly oxylipins, to the central physiological function of vasoregulation. This novel pathway opens new therapeutic perspectives.

physiology↗

bioRxiv2019

Identification of TMEM206 proteins as pore of ASOR acid-sensitive chloride channels

Acid-sensing ion channels have important functions in physiology and pathology, but the molecular composition of acid-activated anion channels had remained unclear. We now used a genome-wide siRNA screen to molecularly identify the widely expressed acid-sensitive outwardly-rectifying ASOR chloride channel. ASOR is formed by TMEM206 proteins which display two transmembrane domains (TMs) and are expressed at the plasma membrane. Ion permeation-changing mutations along the length of TM2 and at the end of TM1 suggest that these segments line ASORs pore. While not belonging to a gene family, TMEM206 has orthologs in probably all vertebrates. Currents from evolutionarily distant orthologs share activation by protons, a feature essential for ASORs role in acid-induced cell death. TMEM206 defines a novel class of ion channels. Its identification will help to understand its physiological roles and the diverse ways by which anion-selective pores can be formed.

physiology↗