Abstract
The physiological functions controlled by T-type channels are intrinsically dependent on their gating properties, and alteration of T-type channel activity is linked to several human disorders. Therefore, it is essential to develop a clear understanding of the structural determinants responsible for the unique gating features of T-type channels. Here, we have investigated the specific role of the carboxy terminal region by creating a series a deletion constructs expressed in tsA-201 cells and analyzing them by patch clamp electrophysiology. Our data reveal that the proximal region of the carboxy terminus contains a structural determinant essential for shaping several gating aspects of Cav3.3 channels, including voltage-dependence of activation and inactivation, inactivation kinetics, and coupling between the voltage sensing and the pore opening of the channel. Altogether, our data are consistent with a model in which the carboxy terminus stabilizes the channel in a closed state.
Highlights
Low voltage-activated T-type calcium channels support essential functions both in excitable and nonexcitable cells [1]
We demonstrate that the initial proximal region of the C-terminus contains a stretch of 20 amino acids that is highly conserved among the three T-type channel isoforms and essential for setting the gating of Cav3.3 channels
Voltage-dependent gating of T-type channels is an essential determinant of physiological functions supported by these channels
Summary
Low voltage-activated T-type calcium channels support essential functions both in excitable and nonexcitable cells [1]. The molecular cloning of T-type channels has revealed the existence of three distinct channel isoforms, namely Cav3.1 [2], Cav3.2 [3], and Cav3.3 [4]. Cav3.1 and Cav3.2 are rather ubiquitously expressed and are found in the nervous system, neuroendocrine cells, cardiovascular system, and even the reproductive system [1]. Cav3.3 channels are mostly expressed in the nervous system, the presence of the channel in neuroendocrine tissues has been suggested. Cav3.3 channels are highly expressed in the olfactory bulb, cortex, midbrain/diencephalon, and in the cerebellum, and to a lesser extent in the hippocampus and pons/medulla [5,6,7]. Cav3.3 channels were documented in rat pancreatic beta cells [8], human spermatogenic cells [9], and in interstitial cells of Cajal in rat bladder [10]
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