Cardiac Hypertrophy Caused by Hyperthyroidism in Rats: Role of ATF-6 and TRPC1 Channels

Hyperthyroidism influences the development of cardiac hypertrophy. Transient receptor potential canonical channels (TRPCs) and ER stress are regarded as critical pathways in cardiac hypertrophy.Hence, we aimed to identify the TRPCs associated with ER stress in hyperthyroidism-induced cardiac hypertrophy.20 adult Wistar albino male rats were used in the study.The control group was fed with standard food and tap water. The group with hyperthyroidism was also fed with standard rat food, along with tap water that contained 12 mg/L of thyroxine for four weeks.At the end of the fourth week, the serum-free T3, T4, and TSH levels of the groups were measured. The left ventricle of each rat was used for histochemistry, immunohistochemistry, western blot, total antioxidant capacity (TAC), and total oxidant status (TOS) analysis. As per our results, ATF-6, IRE-1, and TRPC1, which play a significant role in cardiac hypertrophy caused by hyperthyroidism, showed increased activation. Moreover, TOS and fT3 levels increased, while TAC and TSH levels decreased. With the help of the literature review in our study, we could, for the first time, indicate that the increased activation, in particular of ATF-6, IRE-1, and TRPC1-induced deterioration of the Ca2+ ion balance, leads to hypertrophy in hyperthyroidism due to heart failure.

Electrophysiological Properties of Endogenous Single Ca2+ Activated Cl− Channels Induced by Local Ca2+ Entry in HEK293

Microdomains formed by proteins of endoplasmic reticulum and plasma membrane play a key role in store-operated Ca2+ entry (SOCE). Ca2+ release through inositol 1,4,5-trisphosphate receptor (IP3R) and subsequent Ca2+ store depletion activate STIM (stromal interaction molecules) proteins, sensors of intraluminal Ca2+, which, in turn, open the Orai channels in plasma membrane. Downstream to this process could be activated TRPC (transient receptor potential-canonical) calcium permeable channels. Using single channel patch-clamp technique we found that a local Ca2+ entry through TRPC1 channels activated endogenous Ca2+-activated chloride channels (CaCCs) with properties similar to Anoctamin6 (TMEM16F). Our data suggest that their outward rectification is based on the dependence from membrane potential of both the channel conductance and the channel activity: (1) The conductance of active CaCCs highly depends on the transmembrane potential (from 3 pS at negative potentials till 60 pS at positive potentials); (2) their activity (NPo) is enhanced with increasing Ca2+ concentration and/or transmembrane potential, conversely lowering of intracellular Ca2+ concentration reduced the open state dwell time; (3) CaCC amplitude is only slightly increased by intracellular Ca2+ concentration. Experiments with Ca2+ buffering by EGTA or BAPTA suggest close local arrangement of functional CaCCs and TRPC1 channels. It is supposed that Ca2+-activated chloride channels are involved in Ca2+ entry microdomains.

Trpc1 as the Missing Link Between the Bmp and Ca2+ Signalling Pathways During Neural Specification in Amphibians

In amphibians, the inhibition of bone morphogenetic protein (BMP) in the dorsal ectoderm has been proposed to be responsible for the first step of neural specification, called neural induction. We previously demonstrated that in Xenopus laevis embryos, the BMP signalling antagonist, noggin, triggers an influx of Ca2+ through voltage-dependent L-type Ca2+ channels (LTCCs), mainly via CaV1.2, and we showed that this influx constitutes a necessary and sufficient signal for triggering the expression of neural genes. However, the mechanism linking the inhibition of BMP signalling with the activation of LTCCs remained unknown. Here, we demonstrate that the transient receptor potential canonical subfamily member 1, (Trpc1), is an intermediate between BMP receptor type II (BMPRII) and the CaV1.2 channel. We show that noggin induces a physical interaction between BMPRII and Trpc1 channels. This interaction leads to the activation of Trpc1 channels and to an influx of cations, which depolarizes the plasma membrane up to a threshold sufficient to activate Cav1.2. Together, our results demonstrate for the first time that during neural induction, Ca2+ entry through the CaV1.2 channel results from the noggin-induced interaction between Trpc1 and BMPRII.