Contributions of T-type calcium channel isoforms to neuronal firing

Cain, Stuart M.; Snutch, Terrance P.

doi:10.4161/chan.4.6.14106

Cited by 167 publications

(157 citation statements)

References 54 publications

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“…There are three Cav3 pore-forming proteins (Cav3.1, Cav3.2, and Cav3.3 subunits) all displaying typical properties of T-type channels when expressed in heterologous cell systems (3,16). Among them, the Cav3.2 channel seems to be particularly sensitive to various types of regulation, including phosphorylation.…”

mentioning

confidence: 99%

Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

Blesneac

Chemin

Bidaud

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Phosphorylation is a major mechanism regulating the activity of ion channels that remains poorly understood with respect to T-type calcium channels (Cav3). These channels are low voltage-activated calcium channels that play a key role in cellular excitability and various physiological functions. Their dysfunction has been linked to several neurological disorders, including absence epilepsy and neuropathic pain. Recent studies have revealed that T-type channels are modulated by a variety of serine/threonine protein kinase pathways, which indicates the need for a systematic analysis of T-type channel phosphorylation. Here, we immunopurified Cav3.2 channels from rat brain, and we used high-resolution MS to construct the first, to our knowledge, in vivo phosphorylation map of a voltage-gated calcium channel in a mammalian brain. We identified as many as 34 phosphorylation sites, and we show that the vast majority of these sites are also phosphorylated on the human Cav3.2 expressed in HEK293T cells. In patch-clamp studies, treatment of the channel with alkaline phosphatase as well as analysis of dephosphomimetic mutants revealed that phosphorylation regulates important functional properties of Cav3.2 channels, including voltage-dependent activation and inactivation and kinetics. We also identified that the phosphorylation of a locus situated in the loop I-II S442/S445/T446 is crucial for this regulation. Our data show that Cav3.2 channels are highly phosphorylated in the mammalian brain and establish phosphorylation as an important mechanism involved in the dynamic regulation of Cav3.2 channel gating properties.T-type calcium channel | Cav3.2 subunit | patch clamp | mass spectrometry | phosphorylation V oltage-gated calcium channels (L-, N-, P/Q-, R-, and T-types) mediate calcium entry in many different cell types in response to membrane depolarization and action potentials. Calcium influx through these channels serves as an important second messenger of electrical signaling, initiating a variety of cellular events and physiological functions (1, 2). Among the family of voltage-gated calcium channels, T-type calcium channels (Cav3 family) have unique electrophysiological properties, because they display low voltageactivated calcium currents with rapid activation/inactivation kinetics. In neurons, small changes in the membrane potential near the resting potential can activate T-type channels, favoring further membrane depolarization and repetitive firing of action potentials (3-5). These unique gating properties of T-type channels make them important in many different processes, including neuronal spontaneous firing and pacemaker activities, rebound burst firing, sleep rhythms, sensory processing, and neuronal differentiation, as well as in pathological conditions, such as epilepsy and neuropathic pain (6).To properly assure this plurality of physiological functions, a tight control of T-type calcium channels is necessary. An important regulatory mechanism is phosphorylation, the fastest and most frequent posttranslat...

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confidence: 99%

Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

Blesneac

Chemin

Bidaud

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In other words, the momentary decrease in goal-directed activation associated with the local abrupt-onset appeared to subsequently boost neuronal excitability, acting to drive activation toward saccade threshold. This pattern is reminiscent of the action of certain types of neuronal ion channels, for example, T-type calcium channels (Cain & Snutch, 2010;Huguenard, 1996). These channels will inactivate during steady depolarization (Isope, Hildebrand, & Snutch, 2010), which in our paradigm would occur during presentation of the array ( Figure 3A), which produces a persistent goal signal (25% probability) before the target is revealed.…”

Section: Underlying Mechanismmentioning

confidence: 93%

Competitive Integration of Visual and Goal-related Signals on Neuronal Accumulation Rate: A Correlate of Oculomotor Capture in the Superior Colliculus

White

Marino

Boehnke

et al. 2013

Journal of Cognitive Neuroscience

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Abstract■ The mechanisms that underlie the integration of visual and goal-related signals for the production of saccades remain poorly understood. Here, we examined how spatial proximity of competing stimuli shapes goal-directed responses in the superior colliculus (SC), a midbrain structure closely associated with the control of visual attention and eye movements. Monkeys were trained to perform an oculomotor-capture task [Theeuwes, J., Kramer, A. F., Hahn, S., Irwin, D. E., & Zelinsky, G. J. Influence of attentional capture on oculomotor control. Journal of Experimental Psychology. Human Perception and Performance, 25,[1595][1596][1597][1598][1599][1600][1601][1602][1603][1604][1605][1606][1607][1608] 1999], in which a target singleton was revealed via an isoluminant color change in all but one item. On a portion of the trials, an additional salient item abruptly appeared near or far from the target. We quantified how spatial proximity between the abrupt-onset and the target shaped the goal-directed response. We found that the appearance of an abrupt-onset near the target induced a transient decrease in goal-directed discharge of SC visuomotor neurons. Although this was indicative of spatial competition, it was immediately followed by a rebound in presaccadic activation, which facilitated the saccadic response (i.e., it induced shorter saccadic RT). A similar suppression also occurred at most nontarget locations even in the absence of the abrupt-onset. This is indicative of a mechanism that enabled monkeys to quickly discount stimuli that shared the common nontarget feature. These results reveal a pattern of excitation/inhibition across the SC visuomotor map that acted to facilitate optimal behavior-the short duration suppression minimized the probability of capture by salient distractors, whereas a subsequent boost in accumulation rate ensured a fast goal-directed response. Such nonlinear dynamics should be incorporated into future biologically plausible models of saccade behavior. ■

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“…In the end of discharge hyperpolarization appears, bringing about closure of inactivated calcium channels [112]. It is essential as depolarization is possible only when calcium channels are closed (deactivated) [115].…”

Section: Calcium Channelsmentioning

confidence: 99%

“…(24) It is a single burst of action potential. If a cell is more depolarized than -60mV for 50 -100 msec, calcium channels are inactivated, and the cell responds to an excitatory input in tonic mode [115,116]. Fig.…”

Section: Calcium Channelsmentioning

confidence: 99%

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Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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Contributions of T-type calcium channel isoforms to neuronal firing

Cited by 167 publications

References 54 publications

Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties

Competitive Integration of Visual and Goal-related Signals on Neuronal Accumulation Rate: A Correlate of Oculomotor Capture in the Superior Colliculus

Ion Channels as Drug Targets in Central Nervous System Disorders

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