T-type Channels Become Highly Permeable to Sodium Ions Using an Alternative Extracellular Turret Region (S5-P) Outside the Selectivity Filter

Senatore, Adriano; Guan, Wendy; Boone, Adrienne N.; Spafford, J. David

doi:10.1074/jbc.m114.551473

Cited by 32 publications

(114 citation statements)

References 47 publications

Supporting

Mentioning

112

Contrasting

Order By: Relevance

“…30 Ca v 3 T-type channels in invertebrates have a differing sodium and calcium ion permeability through alternative splicing, which is not present in the more exclusively calcium-selective Ca v 3 channels in vertebrates. 27 The greater flexibility in ion selectivity may relate to the presence of ~4× fewer numbers of 4x6TM channels to draw upon in invertebrate genomes for structural and functional diversification.…”

Section: Discussionmentioning

confidence: 99%

“…9 The heart of snails, for example, completely lack sodium-dependent action potentials and expression of Na v 1 sodium channels. 27 NALCN is thus likely working mostly as a calcium sensor in muscle, to sense the ion fluxes during contraction that are mostly carried by calcium ions.…”

Section: Downloaded By [University Of Saskatchewan Library] At 19:04 mentioning

confidence: 99%

“…While these four residues play critical roles in governing sodium and calcium selectivity of 4x6TM channels, each re-entrant pore is not equal in its contribution as in symmetrical (homo-multimeric) potassium channels, and furthermore the divergent residues of the re-entrant P-loops outside of the selectivity filter residues also can influence ion selectivity. 26,27 The selectivity filter consists of dipole pairs of characteristic negatively charged glutamate residues projecting into pore, providing an EEEE selectivity filter filter and form a C-terminal helical bundle that meet like an inverted teepee serving as a channel gate to occlude ion passage at their cytoplasmic ends. 23 X-ray structures from Roderick Mackinnon elegantly illustrate the concept of potassium channel permeation.…”

Section: Structural Features Of Nalcn Calcium Channels and Sodium Chmentioning

confidence: 99%

See 2 more Smart Citations

A uniquely adaptable pore is consistent with NALCN being an ion sensor

Senatore

Spafford

2013

Channels

Self Cite

View full text Add to dashboard Cite

NALCN is an intriguing, orphan ion channel among the 4x6TM family of related voltage-gated cation channels, sharing a common architecture of four homologous domains consisting of six transmembrane helices, separated by three cytoplasmic linkers and delimited by N and C-terminal ends. NALCN is one of the shortest 4x6TM family members, lacking much of the variation that provides the diverse palate of gating features, and tissue specific adaptations of sodium and calcium channels. NALCN's most distinctive feature is that that it possesses a highly adaptable pore with a calcium-like EEEE selectivity filter in radially symmetrical animals and a more sodium-like EEKE or EKEE selectivity filter in bilaterally symmetrical animals including vertebrates. Two lineages of animals evolved alternative calcium-like EEEE and sodium-like EEKE / EKEE pores, spliced to regulate NALCN functions in differing cellular environments, such as muscle (heart and skeletal) and secretory tissue (brain and glands), respectively. A highly adaptable pore in an otherwise conserved ion channel in the 4x6TM channel family is not consistent with a role for NALCN in directly gating a significant ion conductance that can be either sodium ions or calcium ions. NALCN was proposed to be an expressible Gd ( 3+) -sensitive, NMDG (+) -impermeant, non-selective and ohmic leak conductance in HEK-293T cells, but we were unable to distinguish these reported currents from leaky patch currents (ILP) in control HEK-293T cells. We suggest that NALCN functions as a sensor for the much larger UNC80/UNC79 complex, in a manner consistent with the coupling mechanism known for other weakly or non-conducting 4x6TM channel sensor proteins such as Nax or Cav 1.1. We propose that NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Downloaded By [University Of Saskatchewan Library] At 19:04 mentioning

confidence: 99%

Section: Structural Features Of Nalcn Calcium Channels and Sodium Chmentioning

confidence: 99%

See 1 more Smart Citation

A uniquely adaptable pore is consistent with NALCN being an ion sensor

Senatore

Spafford

2013

Channels

Self Cite

View full text Add to dashboard Cite

show abstract

“…My laboratory has discovered a potential determinant for generating more selective blocking antagonists for each of the three T-type channels. We recently found that T-type channels have an extracellular, cysteine scaffold above the pore of T-type channels that can alter the accessibility of drugs and is highly variable among T-type channels [7]. This extracellular scaffold could be a useful determinant to develop more selective T-type channel blockers.…”

Section: "No Medicines Clinicallymentioning

confidence: 99%

“…T-type channels are at their highest density in the human body within the thalamus intersecting the circuits underlying normal sleep patterns and the abnormal, pathological rhythms during absence epilepsy. that are selective for the inflow of positive calcium ions (and some sodium ions [7]) generating excitability across nerve cell membranes. T-type channels are 'first responders' from the resting state with a low voltage threshold for ion gating [6].…”

mentioning

confidence: 99%

Cav3 T-Type Channels As Drug Targets For Treating Epilepsy

2014

Self Cite

View full text Add to dashboard Cite

Limulus and heart rhythm

et al. 2018

View full text Add to dashboard Cite

Great interest in the comparative physiology of hearts and their functions in Animalia has emerged with classic papers on Limulus polyphemus and mollusks. The recurrent cardiac activity-heart rate-is the most important physiological parameter and when present the kardia (Greek) is vital to the development of entire organs of the organisms in the animal kingdom. Extensive studies devoted to the regulation of cardiac rhythm in invertebrates have revealed that the basics of heart physiology are comparable to mammals. The hearts of invertebrates also beat spontaneously and are supplied with regulatory nerves: either excitatory or inhibitory or both. The distinct nerves and the source of excitation/inhibition at the level of single neurons are described for many invertebrate genera. The vertebrates and a majority of invertebrates have myogenic hearts, whereas the horseshoe crab L. polyphemus and a few other animals have a neurogenic cardiac rhythm. Nevertheless, the myogenic nature of heartbeat is precursor, because the contraction of native and stem-cellderived cardiomyocytes does occur in the absence of any neural elements. Even in L. polyphemus, the heart rhythm is myogenic at embryonic stages.

show abstract

T-type Channels Become Highly Permeable to Sodium Ions Using an Alternative Extracellular Turret Region (S5-P) Outside the Selectivity Filter

Cited by 32 publications

References 47 publications

A uniquely adaptable pore is consistent with NALCN being an ion sensor

A uniquely adaptable pore is consistent with NALCN being an ion sensor

Cav3 T-Type Channels As Drug Targets For Treating Epilepsy

Limulus and heart rhythm

Contact Info

Product

Resources

About