Engineered calmodulins reveal the unexpected eminence of Ca
            <sup>2+</sup>
            channel inactivation in controlling heart excitation

Alseikhan, Badr A.; DeMaria, Carla D.; Colecraft, Henry M.; Yue, David T.

doi:10.1073/pnas.262372999

Cited by 179 publications

(200 citation statements)

References 44 publications

Supporting

Mentioning

186

Contrasting

Order By: Relevance

“…Functional studies indicate lobe-specific tasks for CaM in Ca V regulation 9,12,16,17,23 . The interactions that bring about lobe-specific regulation by CaM have remained obscure despite the investigation of an abundance of mutations to the IQ domain [13][14][15]17,18,32 .…”

Section: Discussionmentioning

confidence: 99%

“…Elegant experiments have demonstrated that CDI and CDF are controlled independently by the abilities of the N-terminal and C-terminal CaM lobes (the N lobe and C lobe) to bind calcium 9,10,12,16,23 . CDI is present in both L-type (Ca V 1.2) and non-L-type (Ca V 2.1, Ca V 2.2 and Ca V 2.3) channels but arises from the action of opposite CaM lobes in these two cases 9,23 .…”

Section: Competing Interests Statementmentioning

confidence: 99%

“…Although Ca 2+ /C lobe has an established role in Ca V 1.2 CDI 12,16,17 , no role has yet been defined for Ca 2+ /N lobe. Therefore, we tested whether the crystallographically observed Ca 2+ /N lobe interface has a role in channel function by using two-electrode voltage clamp to interrogate mutant channels that were heterologously expressed in Xenopus laevis oocytes.…”

Section: N Lobe Anchors Have a Role In Cdfmentioning

confidence: 99%

“…However, Ca 2+ /N lobe may occupy this position in channel functional states in which the N lobe is loaded with calcium but the C lobe is in the apo state. This property may be particularly relevant for Ca V 2s, where functional experiments have demonstrated that CaM mutants that have diminished C lobe calcium binding but preserve N lobe calcium binding maintain CDI 9,11,23 .Functional studies indicate lobe-specific tasks for CaM in Ca V regulation 9,12,16,17,23 . The interactions that bring about lobe-specific regulation by CaM have remained obscure despite the investigation of an abundance of mutations to the IQ domain [13][14][15]17,18,32 .…”

mentioning

confidence: 99%

See 3 more Smart Citations

Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain–Ca2+/calmodulin complex

Petegem

Chatelain

Minor

2005

Nat Struct Mol Biol

227

390

View full text Add to dashboard Cite

Changes in activity-dependent calcium flux through voltage-gated calcium channels (Ca V s) drive two self-regulatory calcium-dependent feedback processes that require interaction between Ca 2+ / calmodulin (Ca 2+ /CaM) and a Ca V channel consensus isoleucine-glutamine (IQ) motif: calciumdependent inactivation (CDI) and calcium-dependent facilitation (CDF). Here, we report the highresolution structure of the Ca 2+ /CaM-Ca V 1.2 IQ domain complex. The IQ domain engages hydrophobic pockets in the N-terminal and C-terminal Ca 2+ /CaM lobes through sets of conserved 'aromatic anchors.' Ca 2+ /N lobe adopts two conformations that suggest inherent conformational plasticity at the Ca 2+ /N lobe-IQ domain interface. Titration calorimetry experiments reveal competition between the lobes for IQ domain sites. Electrophysiological examination of Ca 2+ /N lobe aromatic anchors uncovers their role in Ca V 1.2 CDF. Together, our data suggest that Ca V subtype differences in CDI and CDF are tuned by changes in IQ domain anchoring positions and establish a framework for understanding CaM lobe-specific regulation of Ca V s.Voltage-gated calcium channels are the ion channels that define excitable cells 1 . These channels control cellular calcium entry in response to changes in membrane potential and are pivotal in the generation of cardiac action potentials, excitation-contraction coupling, hormone and neurotransmitter release and activity-dependent transcription initiation 1,2 . Ca V s are multisubunit complexes composed of three essential channel subunits 2 , Ca V α 1 , Ca V β and Ca V α 2 δ, plus the ubiquitous intracellular calcium sensor calmodulin (CaM) 3 . An additional subunit, Ca V γ, is associated with skeletal muscle channels, but its general importance in other tissues is unsettled 4 .The Ca V α 1 subunits are single polypeptide chains of ∼1,800-2,200 residues in which the ion-conducting pore is formed from four homologous repeats that each bear six transmembrane segments 2 . There are three Ca V subfamilies, which have diverse physiological and pharmacological properties that depend largely on the Ca V α 1 -subunit: Ca V 1.x (L-type), Ca V 2.x (2.1, P/Q-type; 2.2, N-type; 2.3, R-type) and Ca V 3.x (T-type) 1 . Large interdomain intracellular loops bridge the four transmembrane repeats of the Ca V α 1 subunit and serve as docking sites for auxiliary subunits and regulatory molecules that Competing Interests Statement:The authors declare that they have no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access control channel activity and connect Ca V channels to larger macromolecular complexes and cellular signaling pathways 5,6 .Calcium influx is a potent activator of intracellular signaling pathways but is toxic in excess 1,7 . Because Ca V s are major sources of calcium influx, Ca V activity is strongly controlled by both self-regulatory and extrinsic mechanisms that tune channel action in response to electrical...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Competing Interests Statementmentioning

confidence: 99%

Section: N Lobe Anchors Have a Role In Cdfmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain–Ca2+/calmodulin complex

Petegem

Chatelain

Minor

2005

Nat Struct Mol Biol

227

390

View full text Add to dashboard Cite

show abstract

“…This pattern could provide a distinctive signature for an analogous involvement of CaM in native P-type currents. However, the challenge of culturing postnatal Purkinje neurons made it difficult to deliver mutant CaM molecules by plasmid transfection or viral transduction (DeMaria et al, 2001;Alseikhan et al, 2002;Lee et al, 2003), so we acutely introduced recombinant CaM proteins via patch pipette. If exchange of recombinant CaMs were sufficiently rapid (minutes), then the telltale pattern of CaM lobe-specific elimination of CDF should develop during individual recordings.…”

Section: Calmodulin Triggers Neuronal Camentioning

confidence: 99%

Developmental Activation of Calmodulin-Dependent Facilitation of Cerebellar P-Type Ca²⁺Current

Chaudhuri¹,

Alseikhan²,

Sheng³

et al. 2005

J. Neurosci.

View full text Add to dashboard Cite

-dependent facilitation (CDF) of channel opening. This facilitation occurs when local Ca 2ϩ influx through individual channels selectively activates the C-terminal lobe of calmodulin. In neurons, however, such calmodulin-mediated processes have yet to be detected, and CDF of native P-type current has thus far appeared different, arguably triggered by other Ca 2ϩ sensing molecules. Here, in cerebellar Purkinje somata abundant with prototypic P-type channels, we find that the C-terminal lobe of calmodulin does produce CDF, and such facilitation augments Ca 2ϩ entry during stimulation by repetitive action-potential and complex-spike waveforms. Beyond recapitulating key features of recombinant channels, these neurons exhibit an additional modulatory dimension: developmental upregulation of CDF during postnatal week 2. This phenomenon reflects increasing somatic expression of Ca V 2.1 splice variants that manifest CDF and progressive dendritic targeting of variants lacking CDF. Calmodulin-triggered facilitation is thus fundamental to native Ca V 2.1 and rapidly enhanced during early development.

show abstract

Calcium signaling via voltage‐dependent L‐type Ca²⁺ channels

Naguro

Adachi‐Akahane

Ichijo

2004

Signal Transduction

View full text Add to dashboard Cite

In excitable cells such as muscles and neurons, the voltage-dependent L-type Ca 2+ channel is one of the most important pathways for Ca 2+ influx from extracellular space in response to the cell membrane depolarization. Ca 2+ ion through this channel works as a Ca 2+ signal that regulates fast (on time scale of milliseconds; e.g. muscle contraction) and long-term (on a time scale of days or weeks; e.g. gene expression) cellular responses. Many important signal molecules are activated via Ca 2+ signal, such as Ca 2+ -dependent protease (calpain), calcium/calmodulin dependent kinases (CaMKs), phosphatase (calcineurin), and mitogen-activated protein kinases (MAPKs). They are activated by temporally and spatially restricted Ca 2+ signals, thus strictly regulated in native tissues. Many kinds of Ca 2+ channels are involved in the rise of the intracellular Ca 2+ concentration. They are not mere routes of Ca 2+ influx but also machineries that decide which specific signal cascade should be activated. Recently, the molecular mechanisms by which Ca 2+ influx through L-type Ca 2+ channels can activate specific signal cascades have been clarified. In this review, we describe the role of Ca 2+ signaling via L-type Ca 2+ channels particularly in cardiac myocytes and neurons with emphasis on the mechanisms underlying the activation of the specific Ca 2+ signals by the L-type Ca 2+ channel machinery.

show abstract

Engineered calmodulins reveal the unexpected eminence of Ca ²⁺ channel inactivation in controlling heart excitation

Cited by 179 publications

References 44 publications

Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain–Ca2+/calmodulin complex

Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain–Ca2+/calmodulin complex

Developmental Activation of Calmodulin-Dependent Facilitation of Cerebellar P-Type Ca²⁺Current

Calcium signaling via voltage‐dependent L‐type Ca²⁺ channels

Contact Info

Product

Resources

About

Engineered calmodulins reveal the unexpected eminence of Ca 2+ channel inactivation in controlling heart excitation

Cited by 179 publications

References 44 publications

Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain–Ca2+/calmodulin complex

Insights into voltage-gated calcium channel regulation from the structure of the CaV1.2 IQ domain–Ca2+/calmodulin complex

Developmental Activation of Calmodulin-Dependent Facilitation of Cerebellar P-Type Ca2+Current

Calcium signaling via voltage‐dependent L‐type Ca2+ channels

Contact Info

Product

Resources

About

Engineered calmodulins reveal the unexpected eminence of Ca ²⁺ channel inactivation in controlling heart excitation

Developmental Activation of Calmodulin-Dependent Facilitation of Cerebellar P-Type Ca²⁺Current

Calcium signaling via voltage‐dependent L‐type Ca²⁺ channels