Functional properties of a neuronal class C L-type calcium channel

Tomlinson, W.Jeffrey; Stea, Anthony; Bourinet, Emmanuel; Charnet, Pierre; Nargeot, Joël; Snutch, Terry P.

doi:10.1016/0028-3908(93)90006-o

Cited by 155 publications

(119 citation statements)

References 44 publications

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“…Although ␤ subunits appear to affect the rate of L-type channel inactivation, steady-state inactivation seems to be less dependent on ␤ subunit coexpression than non-L-type channels (9,18,(23)(24). These data suggest that there are some intrinsic molecular determinants differing between L-type and non-L-type Ca v channels in the control of inactivation by ␤ subunits.…”

Section: Structural Differences Between Aid Sequences and Potentialmentioning

confidence: 80%

The Interaction between the I-II Loop and the III-IV Loop of Cav2.1 Contributes to Voltage-dependent Inactivation in a β-Dependent Manner

Geib¹,

Sandoz²,

Cornet³

et al. 2002

Journal of Biological Chemistry

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We have investigated the molecular mechanisms whereby the I-II loop controls voltage-dependent inactivation in P/Q calcium channels. We demonstrate that the I-II loop is localized in a central position to control calcium channel activity through the interaction with several cytoplasmic sequences; including the III-IV loop. Several experiments reveal the crucial role of the interaction between the I-II loop and the III-IV loop in channel inactivation. First, point mutations of two amino acid residues of the I-II loop of Ca v 2.1 (Arg-387 or Glu-388) facilitate voltage-dependent inactivation. Second, overexpression of the III-IV loop, or injection of a peptide derived from this loop, produces a similar inactivation behavior than the mutated channels. Third, the III-IV peptide has no effect on channels mutated in the I-II loop. Thus, both point mutations and overexpression of the III-IV loop appear to act similarly on inactivation, by competing off the native interaction between the I-II and the III-IV loops of Ca v 2.1. As they are known to affect inactivation, we also analyzed the effects of ␤ subunits on these interactions. In experiments in which the ␤ 4 subunit is co-expressed, the III-IV peptide is no longer able to regulate channel inactivation. We conclude that (i) the contribution of the I-II loop to inactivation is partly mediated by an interaction with the III-IV loop and (ii) the ␤ subunits partially control inactivation by modifying this interaction. These data provide novel insights into the mechanisms whereby the ␤ subunit, the I-II loop, and the III-IV loop altogether can contribute to regulate inactivation in high voltage-activated calcium channels.The influx of calcium through voltage-gated calcium channels controls a variety of cellular processes ranging from membrane excitability and synaptic efficacy to gene expression. Both the amplitude and the duration of the calcium influx shape the spatio-temporal efficacy of calcium signaling. A tight control of both processes is needed to avoid long term increases in intracellular calcium levels, which are cytotoxic to neurons. Although the control of calcium entry can be achieved in several ways, inactivation of voltage-gated calcium channels appears to represent a key molecular process. For instance, inactivation is considered as a candidate mechanism for synaptic depression (1, 2). Inasmuch as there are several calcium channel types, there are also several inactivation behaviors. L-type calcium channels inactivate slowly, whereas the neuronal N-, P/Q-, and R-type channels inactivate faster. These fundamental differences are linked to the pore-forming Ca v subunit, which contains the major molecular determinants for inactivation, although auxiliary subunits can play a regulatory function in this process.

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Section: Structural Differences Between Aid Sequences and Potentialmentioning

confidence: 80%

The Interaction between the I-II Loop and the III-IV Loop of Cav2.1 Contributes to Voltage-dependent Inactivation in a β-Dependent Manner

Geib¹,

Sandoz²,

Cornet³

et al. 2002

Journal of Biological Chemistry

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“…Although the immunohistochemical data support the presence of Ca V 1.3 channels on dendritic membranes (Carlin et al, 2000b), this is based on the presence of the α 1 1.3 subunit. The voltage of activation of the channels will depend also on the β and α 2 δ subunits (Williams et al, 1992;Tomlinson et al, 1993), neither of which have yet been identified and classified in motoneurons. Therefore, caution should be exercised in attributing specific biophysical properties to these channels.…”

Section: The Role Of Motoneuron Dendrites In Repetitive Firingmentioning

confidence: 99%

Beginning at the end: Repetitive firing properties in the final common pathway

Brownstone

2006

Progress in Neurobiology

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Since the early 20th century, it has been recognized that motoneurons must fire repetitive trains of action potentials to produce muscle contraction. In 1932, Sir John Eccles, together with Hebbel Hoff, found that action potential spike trains in motor axons were produced by "rhythmic centres", which were within the motoneurons themselves. Two decades later, Eccles attended a Cold Spring Harbor Symposium in NY, USA entitled "The Neuron". Two of the many notable presentations at this symposium were juxtaposed: one by Eccles from the University of Otago, Dunedin, NZL, and the other by J. Walter Woodbury and Harry Patton from the University of Washington, Seattle, USA. Both presentations included data obtained using sharp microelectrodes to study the intracellularly recorded potentials of cat motoneurons. In this review, I discuss some of the events leading up to and surrounding this jointly accomplished advance and proceed to discussion of subsequent studies over 5+ decades that have made use of intracellular recordings from motoneurons to study their repetitive firing behavior. This begins with early descriptions of primary and secondary range firing, and continues to the discovery of dendritic persistent inward currents and their relation to plateau potentials, synaptic amplification, and motoneuronal firing. Following a brief description of the possible mechanisms underlying spike frequency adaptation, I discuss the modulation of repetitive firing properties during various motor behaviors. It has become increasingly clear that the central nervous system has exquisite control of the repetitive firing of motoneurons. Eccles' work laid the foundation for the present-day study of these processes.

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“…Voltage-dependent inactivation of L-type Ca 2ϩ channels containing cloned ␣ 1C is slower than inactivation of P͞Q-type Ca 2ϩ channels containing cloned ␣ 1A expressed with the same auxiliary subunits in Xenopus oocytes (5,6). In addition, N-type and P͞Q-type Ca 2ϩ channels, but not L-type Ca 2ϩ channels, are modulated by neurotransmitter receptors acting through pertussis toxin-sensitive G proteins via membrane-delimited pathways that cause a positive shift in the voltage dependence of channel activation which is reversed by strong depolarization (9)(10)(11)(12).…”

mentioning

confidence: 90%

“…P͞Q-type and N-type Ca 2ϩ channels containing ␣ 1A or ␣ 1B subunits differ from L-type Ca 2ϩ channels containing ␣ 1C or ␣ 1D subunits in voltage-dependent inactivation (5)(6)(7)(8) and in modulation by G proteins (9). Voltage-dependent inactivation of L-type Ca 2ϩ channels containing cloned ␣ 1C is slower than inactivation of P͞Q-type Ca 2ϩ channels containing cloned ␣ 1A expressed with the same auxiliary subunits in Xenopus oocytes (5,6).…”

mentioning

confidence: 96%

Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α _1A subunit

Herlitze

Hockerman

Scheuer

et al. 1997

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

194

176

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Synaptic transmission is regulated by G protein-coupled receptors whose activation releases G protein ␤␥ subunits that modulate presynaptic Ca 2؉ channels. The sequence motif QXXER has been proposed to be involved in the interaction between G protein ␤␥ subunits and target proteins including adenylyl cyclase 2. This motif is present in the intracellular loop connecting domains I and II (L I-II ) of Ca 2؉ channel ␣ 1A subunits, which are modulated by G proteins, but not in ␣ 1C subunits, which are not modulated. Peptides containing the QXXER motif from adenylate cyclase 2 or from ␣ 1A block G protein modulation but a mutant peptide containing the sequence AXXAA does not, suggesting that the QXXER-containing peptide from ␣ 1A can competitively inhibit G␤␥ modulation. Conversion of the R in the QQIER sequence of ␣ 1A to E as in ␣ 1C slows channel inactivation and shifts the voltage dependence of steady-state inactivation to more positive membrane potentials. Conversion of the final E in the QQLEE sequence of ␣ 1C to R has opposite effects on voltage-dependent inactivation, although the changes are not as large as those for ␣ 1A . Mutation of the QQIER sequence in ␣ 1A to QQIEE enhanced G protein modulation, and mutation to QQLEE as in ␣ 1C greatly reduced G protein modulation and increased the rate of reversal of G protein effects. These results indicate that the QXXER motif in L I-II is an important determinant of both voltage-dependent inactivation and G protein modulation, and that the amino acid in the third position of this motif has an unexpectedly large inf luence on modulation by G␤␥. Overlap of this motif with the consensus sequence for binding of Ca 2؉ channel ␤ subunits suggests that this region of L I-II is important for three different modulatory inf luences on Ca 2؉ channel activity.Neuronal voltage-gated Ca 2ϩ channels are involved in multiple cellular functions including neurotranstransmitter release, Ca 2ϩ -mediated regulatory processes, and generation of dendritic action potentials. They consist of complexes of a poreforming ␣ 1 subunit of 190-250 kDa in association with ␣ 2 ␦ and ␤ subunits (1, 2). Electrophysiological and pharmacological studies distinguish at least six classes of Ca 2ϩ channel currents designated L-, N-, P-, Q-, R-, and T-type (2, 3). Ca 2ϩ channels containing ␣ 1C or ␣ 1D subunits are thought to be responsible for L-type currents, ␣ 1B for N-type currents, and ␣ 1A for both P-and Q-type calcium currents (2, 4). A major goal of current research is to correlate the observed differences among the properties of these channel types with the structures of their ␣ 1 subunits.P͞Q-type and N-type Ca 2ϩ channels containing ␣ 1A or ␣ 1B subunits differ from L-type Ca 2ϩ channels containing ␣ 1C or ␣ 1D subunits in voltage-dependent inactivation (5-8) and in modulation by G proteins (9). Voltage-dependent inactivation of L-type Ca 2ϩ channels containing cloned ␣ 1C is slower than inactivation of P͞Q-type Ca 2ϩ channels containing cloned ␣ 1A expressed with the same auxiliary subun...

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Functional properties of a neuronal class C L-type calcium channel

Cited by 155 publications

References 44 publications

The Interaction between the I-II Loop and the III-IV Loop of Cav2.1 Contributes to Voltage-dependent Inactivation in a β-Dependent Manner

The Interaction between the I-II Loop and the III-IV Loop of Cav2.1 Contributes to Voltage-dependent Inactivation in a β-Dependent Manner

Beginning at the end: Repetitive firing properties in the final common pathway

Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α _1A subunit

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Functional properties of a neuronal class C L-type calcium channel

Cited by 155 publications

References 44 publications

The Interaction between the I-II Loop and the III-IV Loop of Cav2.1 Contributes to Voltage-dependent Inactivation in a β-Dependent Manner

The Interaction between the I-II Loop and the III-IV Loop of Cav2.1 Contributes to Voltage-dependent Inactivation in a β-Dependent Manner

Beginning at the end: Repetitive firing properties in the final common pathway

Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α 1A subunit

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Molecular determinants of inactivation and G protein modulation in the intracellular loop connecting domains I and II of the calcium channel α _1A subunit