Unified Mechanisms of Ca2+ Regulation across the Ca2+ Channel Family

Liang, Haoya; DeMaria, Carla D.; Erickson, Michael G.; Mori, Masayuki; Alseikhan, Badr A.; Yue, David T.

doi:10.1016/s0896-6273(03)00560-9

Cited by 291 publications

(410 citation statements)

References 52 publications

Supporting

Mentioning

384

Contrasting

Order By: Relevance

“…Moreover, the percentage of inactivation 300 ms into the test pulse was not different in barium and calcium (not shown). In light of the work of Liang et al (20), these data suggest the intriguing possibility that calcium-dependent inactivation of N-type calcium channels may be dependent on the type of calcium channel ␤ subunit. Moreover, our data suggest that inactivation of N-type channels complexes containing ␤ 3 and ␤ 4 is governed predominantly by a voltage-dependent process.…”

Section: ␤ 3 and ␤ 4 Mediate Distinct Effects On Ca V 22 Gating-mentioning

confidence: 76%

See 1 more Smart Citation

Several Structural Domains Contribute to the Regulation of N-type Calcium Channel Inactivation by the β3 Subunit

Stotz

Barr

McRory

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Calcium channel ␤ subunits are essential regulatory elements of the gating properties of high voltage-activated calcium channels. Co-expression with ␤ 3 subunits typically accelerates inactivation, whereas co-expression with ␤ 4 subunits results in a slowly inactivating phenotype. Here, we have examined the molecular basis of the differential effect of these two subunits on the inactivation characteristics of Ca v 2.2 ؉ ␣ 2 -␦ 1 N-type calcium channels by creating a series of 22 chimeric ␤ subunits that are based on various combinations of variable and conserved regions of the parent ␤ subunit isoforms. Our data show that replacement of the N terminus region of ␤ 4 with a corresponding 14-amino acid stretch of ␤ 3 sequence accelerates the inactivation kinetics to levels seen with wild type ␤ 3 . A similar kinetic speeding is observed by a concomitant substitution of the second conserved and variable regions, but not when these regions are substituted individually, suggesting that 1) the second variable and conserved regions cooperatively regulate N-type calcium channel inactivation and 2) that there are two redundant mechanisms that allow the ␤ 3 subunit to accelerate Ntype channel inactivation. In contrast with previous reports in Ca v 2.1 calcium channels, deletion of the C-terminal region of Ca v 2.2 did not alter the regulation of the channel by wild type and chimeric ␤ subunits. Hence, the molecular underpinnings of ␤ subunit regulation of voltage-gated calcium channels appear to vary with calcium channel subtype.The influx of calcium ions through voltage-gated calcium channels triggers a range of intracellular responses, ranging from gene transcription (1) and activation of second messenger pathways (2, 3) to the release of neurotransmitters from presynaptic nerve termini (4). The amount of calcium entry is regulated by a number of factors, including the intrinsic ability of calcium channels to inactivate in response to prolonged membrane depolarization. It has been suggested that the inactivation process involves the occlusion of the inner mouth of the pore by the intracellular domain I-II linker region of the channel (5-8). This region physically interacts with ancillary calcium channel ␤ subunits (9), which are key regulators of calcium channel inactivation. To date, four different types of calcium channel ␤ subunits have been identified and shown to mediate a spectrum of modulatory actions on the function of high voltage-activated calcium channels. The ␤ 2a subunit uniquely slows the inactivation kinetics of the ␣ 1 subunit through palmitoylation and membrane anchoring of its N terminus region (10 -14), thus possibly restricting the mobility of the putative inactivation gate (for review, see Ref. 6). Despite the absence of palmitoylation sites, the remaining ␤ subunit isoforms mediate differential effects on calcium channel inactivation. For example, channels co-expressed with ␤ 3 subunits typically undergo rapid inactivation, whereas channel complexes containing ␤ 4 tend to inactivate more slowly (12,...

show abstract

Section: ␤ 3 and ␤ 4 Mediate Distinct Effects On Ca V 22 Gating-mentioning

confidence: 76%

“…In this set of experiments, the EGTA concentration in the intracellular recording solution was 1 The abbreviation used is: ANOVA, analysis of variance. dropped to 0.5 mM, and ATP was added such that our internal solution matched that of Liang et al (20). Fig.…”

Section: ␤ 3 and ␤ 4 Mediate Distinct Effects On Ca V 22 Gating-mentioning

confidence: 99%

Several Structural Domains Contribute to the Regulation of N-type Calcium Channel Inactivation by the β3 Subunit

Stotz

Barr

McRory

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Calmodulin has its role in calcium signaling through calciumdependent inactivation or calcium-dependent facilitation. 38,39 It has been shown to bind and act as a regulator of neural excitability in KCNQ 40 and Cav2.1 channels (see Halling et al for a recent review 41 ). The CACNA1A gene encodes the Cav2.1 channel, and it is mutations in this gene that cause the most common form of EA (EA2).…”

Section: Discussionmentioning

confidence: 99%

A novel locus for episodic ataxia:UBR4 the likely candidate

et al. 2013

View full text Add to dashboard Cite

Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca 2 þ protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca 2 þ control within neuronal cells highlights its potential for a role in this form of EA.

show abstract

“…Interestingly, the modes of interaction between CaM and several key Ca 2ϩ mobilization proteins may make them particularly susceptible to PEP-19 because it binds selectively to the C-domain of CaM. For example, voltage-operated Ca 2ϩ channels (46) and the IP 3 receptor (47) rely on selective, sequential, or stepwise interactions with the C-domain of CaM in its apo-or Ca 2ϩ -bound forms.…”

Section: Discussionmentioning

confidence: 99%