A Targeting Motif Involved in Sodium Channel Clustering at the Axonal Initial Segment

Garrido, Juan J.; Giraud, Pierre; Carlier, Edmond; Fernandes, Fanny; Moussif, Anissa; Fache, Marie‐Pierre; Debanne, Dominique; Dargent, Bénédicte

doi:10.1126/science.1085167

Cited by 324 publications

(392 citation statements)

References 28 publications

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“…Clustering of signaling proteins is an intriguing phenomenon of cell biology (42,43). Our present study revealed that clustering of RyRCs into arrays endows interacting channels with unique properties.…”

Section: Discussionmentioning

confidence: 87%

The quantal nature of Ca ²⁺ sparks and in situ operation of the ryanodine receptor array in cardiac cells

Wang

Stern

Rı́os

et al. 2004

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

119

178

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Intracellular Ca 2؉ release in many types of cells is mediated by ryanodine receptor Ca 2؉ release channels (RyRCs) that are assembled into two-dimensional paracrystalline arrays in the endoplasmic͞sarcoplasmic reticulum. However, the in situ operating mechanism of the RyRC array is unknown. Here T he ryanodine receptor Ca 2ϩ release channel (RyRC) is a prototypical member of the Ca 2ϩ release channel superfamily located in the endoplasmic reticulum͞sarcoplasmic reticulum (SR) of eukaryotic cells and plays a pivotal role in intracellular Ca 2ϩ signaling (1-5). Instances of local Ca 2ϩ release, in the form of ''Ca 2ϩ sparks'' or their equivalents, constitute the elementary Ca 2ϩ signaling events in heart, brain, and muscle cells (6-12). Intriguingly, RyRCs in intact cells are almost exclusively found at discrete spark-generating sites, where Ϸ100 channels are assembled into two-dimensional paracrystalline arrays (13)(14)(15). This pattern of RyRC organization seems to be highly conserved from crustaceans to vertebrates (13,15,16), suggesting that array formation is critical to RyRC-mediated Ca 2ϩ signaling in vivo. Thus, understanding array-based RyRC behavior is of fundamental importance for elucidation of intracellular Ca 2ϩ signaling mechanism.Despite a wealth of information on behavior of RyRCs in planar lipid bilayers and other cell-free systems (5,(17)(18)(19)(20), little is known on how RyRCs operate in situ; many fundamental issues regarding the genesis and termination of Ca 2ϩ sparks remain unanswered (5,21,22). Based on in vitro properties of RyRCs, the classic Ca 2ϩ -induced Ca 2ϩ release (CICR) mechanism (23) would predict an all-or-none activation of the RyRC array and an everlasting local Ca 2ϩ release, which cannot explain the prompt termination of Ca 2ϩ sparks and the microstability of intracellular signaling (24, 25). The relatively constant Ca 2ϩ spark rise time (Ϸ10 ms in the heart) indicates a stereotypical open time of RyRCs (25) whereas RyRCs in vitro always follow exponential open-time distributions (5,17,20). The brief spark duration also contrasts sharply with the coupled gating (19) kinetics of RyRCs, in which the open time of physically linked channels acting in unison is prolonged by orders of magnitude (up to 2,500 ms) (20). These paradoxical observations underscore that in vivo operation of RyRCs may involve gating mechanisms that are apparently absent in cell-free systems. Alternatively, the formation of RyRC array may endow the channels with new regulatory mechanisms that are unshared by a corresponding set of solitary RyRCs.In the present study, we sought to investigate RyRC operation in their native arrays. Because intracellular location of RyRC arrays makes them inaccessible to electrophysiological means, we devised an optical approach to analyze the Ca 2ϩ release flux underlying the spark (I spark ) in intact cardiac myocytes. By splitting I spark from individual RyRC arrays into single-channel components, we provided a view of the in situ gating of a single RyRC and demonstrat...

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Section: Discussionmentioning

confidence: 87%

The quantal nature of Ca ²⁺ sparks and in situ operation of the ryanodine receptor array in cardiac cells

Wang

Stern

Rı́os

et al. 2004

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

119

178

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“…However, the most parsimonious interpretation of the data considered together is that Na v 1.5 associates with ankyrin-G and that ankyrin-G is required for cell surface expression of Na v 1.5 in cardiomyocytes. The ankyrin-G-binding motif (VPIAXX-ESD) is conserved among Na v 1.1, 1.2, 1.4, 1.5, and 1.6, and also is required for Na v channel targeting in both neurons (7,8). Therefore, an ankyrin-G-based mechanism for Na v channel targeting appears a conserved feature of both cardiomyocytes and neurons.…”

Section: Discussionmentioning

confidence: 99%

Na_v1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Na_v1.5 on the surface of cardiomyocytes

Mohler

Rivolta

Napolitano

et al. 2004

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

336

357

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We identify a human mutation (E1053K) in the ankyrin-binding motif of Na v1.5 that is associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of Na v1.5. The E1053K mutation abolishes binding of Na v1.5 to ankyrin-G, and also prevents accumulation of Na v1.5 at cell surface sites in ventricular cardiomyocytes. Ankyrin-G and Nav1.5 are both localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na v1.5 coimmunoprecipitates with 190-kDa ankyrin-G from detergent-soluble lysates from rat heart. These data suggest that Na v1.5 associates with ankyrin-G and that ankyrin-G is required for Na v1.5 localization at excitable membranes in cardiomyocytes. Together with previous work in neurons, these results in cardiomyocytes suggest that ankyrin-G participates in a common pathway for localization of voltage-gated Na v channels at sites of function in multiple excitable cell types.arrhythmia ͉ SCN5A ͉ targeting ͉ trafficking ͉ sudden cardiac death

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“…6,19,27 Accommodation between different days could be viewed as a form of activitydependent functional plasticity of the peripheral nervous system. As demonstrated by Debanne et al, 8 the axon should not only be considered as a simple structure that reliably transmits the action potential from the cell body to the nerve terminal: it is also able to express nonsynaptic mechanisms of plasticity, which range from activation and inactivation 7 to dynamic compartmentalization 15,16 of ionic channels. This nonsynaptic form of plasticity could underlie the variability in TF that we observed between different days (mainly between the first day and the subsequent 2 days) and should always be considered in the planning of experimental protocols with serial measurements on the same subject.…”

Section: Cramp and Fasciculation Induction By Transcutaneousmentioning

confidence: 99%

Reliability of a novel neurostimulation method to study involuntary muscle phenomena

Minetto

Botter²,

Ravenni

et al. 2007

Muscle and Nerve

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Experimental methods involving painful electrical stimulation of a peripheral nerve showed the existence of a minimum stimulation frequency capable of inducing cramp, termed "threshold frequency" (TF). Our aim was to test an alternative method to induce fasciculations and cramps electrically. Two daily sessions of electrical stimulation of the abductor hallucis muscle were performed in 19 volunteers on 3 days: stimulation trains of 150 monophasic square pulses (duration 152 s) of increasing frequency (current intensity 30% higher than maximal; frequency of the first trial, 4 pps; recovery between trials, 1 min) were delivered to the main muscle motor point until a cramp developed. Once a cramp was induced the protocol was repeated after 30 min. To verify by electromyography that cramp occurred, a surface electrode array was placed between the motor point and the distal tendon. Ambient and skin temperature were kept constant in all sessions. Fasciculations and cramps were elicited in all subjects. We observed the following median (interquartile range) values of TF: day 1 (session 1), 13 (6) pps; day 1 (session 2), 16 (4) pps; day 2 (session 1), 16 (6) pps; day 2 (session 2), 18 (6) pps; day 3 (session 1), 17 (4) pps; day 3 (session 2), 18 (8) pps. TF intersession intraclass correlation coefficients were 0.82, 0.92, and 0.90 for days 1, 2, and 3, respectively. TF interday intraclass correlation coefficient was 0.85. The absence of pain due to the stimulation and the demonstration of TF reliability support the use of our method for the study of involuntary muscle phenomena.

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A Targeting Motif Involved in Sodium Channel Clustering at the Axonal Initial Segment

Cited by 324 publications

References 28 publications

The quantal nature of Ca ²⁺ sparks and in situ operation of the ryanodine receptor array in cardiac cells

The quantal nature of Ca ²⁺ sparks and in situ operation of the ryanodine receptor array in cardiac cells

Na_v1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Na_v1.5 on the surface of cardiomyocytes

Reliability of a novel neurostimulation method to study involuntary muscle phenomena

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A Targeting Motif Involved in Sodium Channel Clustering at the Axonal Initial Segment

Cited by 324 publications

References 28 publications

The quantal nature of Ca 2+ sparks and in situ operation of the ryanodine receptor array in cardiac cells

The quantal nature of Ca 2+ sparks and in situ operation of the ryanodine receptor array in cardiac cells

Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes

Reliability of a novel neurostimulation method to study involuntary muscle phenomena

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The quantal nature of Ca ²⁺ sparks and in situ operation of the ryanodine receptor array in cardiac cells

The quantal nature of Ca ²⁺ sparks and in situ operation of the ryanodine receptor array in cardiac cells

Na_v1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Na_v1.5 on the surface of cardiomyocytes