Regulation of T-type calcium channels: Signalling pathways and functional implications

Abstract

T-type calcium channels (T-channels) contribute to a wide variety of physiological functions, especially in the cardiovascular and nervous systems. Recent studies using knock-out mouse models have been instrumental in documenting further the role of T-channels in sleep, heartbeat, pain and epilepsy. Importantly, several novel aspects of the regulation of these channels have been identified over the last few years, providing new insights into their physiological and pathophysiological roles. Here, we review recent evidence supporting that the Cav3 subunits of T-channels are modulated by endogenous ligands such as anandamide, zinc, redox and oxidizing agents, as well as G-protein and protein kinases pathways. The study of T-channel mutations associated with childhood absence epilepsy has also revealed new aspects of Cav3 subunit trafficking. Collectively, these findings identify novel regulatory mechanisms involved in the fine tuning of T-channel expression and activity, and offer new directions for the design of novel therapeutic strategies targeting these channels.

Caveolin-3 Regulates Protein Kinase A Modulation of the CaV3.2 (α1H) T-type Ca2+ Channels

“…The intracellular linker region between domains II and III for the Ca v 3.2 channel contains clusters of serine and threonine residues and has been identified as an important region for interaction and regulation of the channel by serine/ threonine kinases and G-protein signaling pathway proteins (3). In this context, it may not be unreasonable to hypothesize an interaction between the N terminus region of Cav-3 and the intracellular loop between domains II and III of the Ca v 3.2 channel.…”

“…T-and L-type calcium currents were recorded from cultured mouse neonatal cardiomyocytes (3)(4)(5) In some experiments neonatal myocytes were pretreated with 10 M myristoylated PKA inhibitor peptide (overnight incubation) to inhibit the PKA activity. The data were collected from a minimum of three different transfections.…”

“…T-type Ca 2ϩ channels (TTCC) 2 are low voltage-activated Ca 2ϩ channels, expressed in various tissues including brain and heart and contribute to a variety of physiological functions such as neuronal excitability, hormone secretion, muscle contraction, and pacemaker activity (1)(2)(3). Molecular cloning studies have identified three different TTCC isoforms, Ca V 3.1 (␣ 1G ), Ca V 3.2 (␣ 1H ), and Ca v 3.3 (␣ 1I ), which functionally can be distinguished by their electrophysiological properties (4 -7).…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…This includes effects of protein kinases (Welsby et al, 2003;Yao et al, 2006;Iftinca et al, 2007), direct binding of G proteins , and phosphatases (Huang et al, 2013a). A detailed description of second messenger regulation of T-type channels has been the focus of several previous review articles (Huc et al, 2009;Iftinca and Zamponi, 2009). Here, we focus on one example in which T-type channel regulation can potentially be exploited as a therapeutic strategy for pain.…”

G Protein-Mediated Inhibition of Cav3.2 T-Type Channels Revisited: Fig. 1.

“…Early studies of hormonal regulation of native T-currents led to conflicting results, some groups reporting stimulation; others, inhibition; and others, no effect. Studies on recombinant channels have partially resolved this conundrum, revealing that regulation is isoform-specific and pathway-dependent (for review, see Huc et al, 2009;Iftinca and Zamponi, 2009). The most highly regulated T-channel isoform to date is Ca v 3.2.…”