T‐types make your clock tick

Voltage gated T-type calcium channels are important regulators of rhythmic activity in the mammalian nervous system. T-type channels are ideally suited towards regulating neuronal excitability for several reasons. First, their voltage dependent gating properties generate a ‘window current’ that allows them to become active near typical neuronal resting membrane potentials. Second, their hyperpolarization induced recovery from inactivation kinetics supports rebound burst activity in many types of neurons (Huguenard & Prince, 1994). Finally, these channels associate with, and regulate, the functions of both calcium activated and voltage gated potassium channels, which in turn shape neuronal firing properties (Turner & Zamponi, 2014). Besides regulating neuronal activity, T-type channels also contribute to low threshold exocytosis through physical coupling to the vesicle release machinery (Weiss et al. 2012). All of these aspects of T-type channel function are of direct relevance to an interesting new study by Yu and colleagues (Yu et al. 2015), reported in this issue of The Journal of Physiology, on the role of T-type channels in the pineal gland. The pineal gland is important for the cyclical release of melatonin, which in turn contributes to the regulation of the mammalian circadian rhythm. However, the cellular and molecular mechanisms that allow the pineal gland to function like a clock remain incompletely understood. Yu and colleagues used electrophysiological recording from cultured pinealocytes to test the hypothesis that the clock function of these cells may rely on cyclical changes in ion channel expression. To make such studies possible, the authors had to examine cultured cells in the absence and the presence of noradrenaline, which mimics what pinealocytes would experience during the day and during night time, respectively. These authors found that noradrenaline treatment induced the expression of a low voltage activated calcium current that can be blocked with the T-type channel inhibitor NNC55-0396 in addition to a high voltage activated current that was sensitive to the L-type channel inhibitor nifedipine. In contrast, only the L-type channel was observed when cells were cultured in ‘day-like’ conditions (i.e. in the absence of noradrenaline). This paper also shows that this Ca2+ channel upregulation required the activation of a β-adrenergic receptor signalling cascade that culminated in a downstream enhancement of Cav3.1 mRNA levels, and also facilitated export of endoplasmic reticulum (ER) localized channel α subunits to the plasma membrane. Indeed, this upregulation of T-type currents was blocked when the cell surface trafficking mechanism was inhibited (Fig. 1). Altogether, these data imply that during the dark cycle, β-adrenergic receptor activation induces expression and membrane trafficking of Cav3.1 channels, rather than a functional modulation of channels that are already at the plasma membrane. Finally, Yu and colleagues showed that the changes in T-type channel expression resulted in changes in resting membrane potential and intracellular calcium levels, but stopped short of demonstrating T-type channel-mediated release of melatonin. During daytime, low levels of noradrenaline predominate and no T-type calcium channels are expressed in the plasma membrane. In contrast, during night time, noradrenaline levels rise. This leads to activation of β-adrenergic receptors (βARs), and protein kinase A (PKA) due to an increase in cyclic AMP (cAMP). PKA then activates Cav3.1 gene transcription leading to: (i) an increased expression of N-type channels in the ER and (ii) export of these channels from the ER to the plasma membrane. The opening of plasma membrane T-type channels leads to calcium entry, and consequently melatonin release. The novel and important findings of Yu and colleagues raise interesting questions about the role of T-type calcium channels in the function of the pineal gland, and thus the establishment and maintenance of circadian rhythms. The resting membrane potential of pinealocytes for T-type Ca2+ channels is approximately −50 mV, which is located within the window current region. Hence, these T-type channels can be active in pinealocytes in their resting state, where they can contribute to changes in membrane potential and promote calcium flux. Work from our own laboratory has revealed that Cav3 calcium channels physically interact with syntaxin 1A, a key protein involved in vesicle release, and that this interaction supports low threshold exocytosis in chromaffin cells (Weiss et al. 2012). We thus speculate that Cav3.1 channels may have a similar excretory function in the pineal gland, i.e. promoting the release of melatonin during the dark cycle. If so, then T-type calcium channels would emerge as important contributors to the regulation of sleep cycles though a mechanism that is distinct from their previously reported role, where Cav3.1 channels in the thalamus can promote/stabilize sleep patterns (Anderson et al. 2005). These new findings should be taken into consideration when designing T-type calcium channel blockers for disorders such as epilepsy and pain. Overall, the findings of Yu and colleagues provide novel insights into the physiology of the pineal gland, and establish Cav3.1 T-type channels as key players in regulating circadian rhythms. None declared. Work in the Zamponi laboratory is supported by a Canada research Chair and grants from the Canadian Institutes for Health Research and the Natural Sciences and Engineering Research Council.

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