Class A Calcium Channel Variants in Pancreatic Islets and Their Role in Insulin Secretion

Ligon, Brooke; Boyd, A. E.; Dunlap, Kathleen

doi:10.1074/jbc.273.22.13905

Cited by 81 publications

(70 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The same kind of variant was also found in rat ␣ 1 2.1 (36). But the nucleotide sequence of mouse ␣ 1 2.1 corresponding to the variant with a longer carboxyl-tail has not been reported so far.…”

Section: Resultsmentioning

confidence: 61%

Novel Cav2.1 Splice Variants Isolated from Purkinje Cells Do Not Generate P-type Ca2+ Current

Tsunemi¹,

Saegusa²,

Ishikawa³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

The ␣ 1 2.1 (␣ 1A ) subunits of P-type and Q-type Ca 2؉ channels are encoded by a single gene, Cacna1a. Although these channels differ in the inactivation kinetics and sensitivity to -agatoxin IVA, the mechanism underlying these differences remains to be clarified. Alternative splicings of the Cacna1a transcript have been postulated to contribute to the respective properties, however, the splice variants responsible for P-type Ca 2؉ channels have not been identified. To explore P-typespecific splice variants, we aimed at cloning ␣ 1 2.1 from isolated mouse Purkinje cells using single-cell reverse transcription-PCR, because in Purkinje cells P-type currents dominate over the whole currents (>95%) with Q-type currents undetected. As a result, two novel splice variants were cloned. Compared with the previously cloned mouse ␣ 1 2.1, two novel variants had additional 48 amino acids at the amino termini, six single amino acid changes, and splicing variations at the exon 46/47 boundary, which produced different carboxyl termini. Furthermore, one variant had one RNA editing site. However, electrophysiological and pharmacological studies indicated that these variants did not generate P-type current in cultured cells. These results suggest that P-type-specific splice variants may exist but that post-translational processing or modification by uncharacterized interacting proteins is also required for generating the P-type current.

show abstract

Section: Resultsmentioning

confidence: 61%

Novel Cav2.1 Splice Variants Isolated from Purkinje Cells Do Not Generate P-type Ca2+ Current

Tsunemi¹,

Saegusa²,

Ishikawa³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…P/Q-type currents became significant only at potentials beyond Ϫ20 mV and peaked at 0 mV. The effect of -agatoxin IVA showed a slow onset and was maximal only 3-4 min after addition (not shown) (20). Timedependent rundown of T-type Ca 2ϩ channels might therefore account for the apparent -agatoxin sensitivity of a current component at voltages more negative than Ϫ20 mV.…”

Section: Voltage-gated Kmentioning

confidence: 99%

Voltage-Gated Ion Channels in Human Pancreatic β-Cells: Electrophysiological Characterization and Role in Insulin Secretion

et al. 2008

View full text Add to dashboard Cite

OBJECTIVE-To characterize the voltage-gated ion channels in human ␤-cells from nondiabetic donors and their role in glucosestimulated insulin release.RESEARCH DESIGN AND METHODS-Insulin release was measured from intact islets. Whole-cell patch-clamp experiments and measurements of cell capacitance were performed on isolated ␤-cells. The ion channel complement was determined by quantitative PCR.RESULTS-Human ␤-cells express two types of voltage-gated K ϩ currents that flow through delayed rectifying (K V 2.1/2.2) and large-conductance Ca 2ϩ -activated K ϩ (BK) channels. Blockade of BK channels (using iberiotoxin) increased action potential amplitude and enhanced insulin secretion by 70%, whereas inhibition of K V 2.1/2.2 (with stromatoxin) was without stimulatory effect on electrical activity and secretion. Voltage-gated tetrodotoxin (TTX)-sensitive Na ϩ currents (Na V 1.6/1.7) contribute to the upstroke of action potentials. Inhibition of Na ϩ currents with TTX reduced glucose-stimulated (6 -20 mmol/l) insulin secretion by 55-70%. Human ␤-cells are equipped with L-(Ca V 1.3), P/Q-(Ca V 2.1), and T-(Ca V 3.2), but not N-or R-type Ca 2ϩ channels. Blockade of L-type channels abolished glucosestimulated insulin release, while inhibition of T-and P/Q-type Ca 2ϩ channels reduced glucose-induced (6 mmol/l) secretion by 60 -70%. Membrane potential recordings suggest that L-and T-type Ca 2ϩ channels participate in action potential generation. Blockade of P/Q-type Ca 2ϩ channels suppressed exocytosis (measured as an increase in cell capacitance) by Ͼ80%, whereas inhibition of L-type Ca 2ϩ channels only had a minor effect.CONCLUSIONS-Voltage-gated T-type and L-type Ca 2ϩ channels as well as Na ϩ channels participate in glucose-stimulated electrical activity and insulin secretion. Ca 2ϩ -activated BK channels are required for rapid membrane repolarization. Exocytosis of insulin-containing granules is principally triggered by Ca 2ϩ influx through P/Q-type Ca 2ϩ channels. Diabetes 57:1618-1628, 2008

show abstract

“…352). Insulin secretion can be blocked by a wide variety of agents, indicating that these spikes activate L-, P-, and R-type currents (238,258,418).…”

Section: Pancreasmentioning

confidence: 99%

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Perez‐Reyes

2003

Physiological Reviews

1,518

1,446

View full text Add to dashboard Cite

T-type Ca2+ channels were originally called low-voltage-activated (LVA) channels because they can be activated by small depolarizations of the plasma membrane. In many neurons Ca2+ influx through LVA channels triggers low-threshold spikes, which in turn triggers a burst of action potentials mediated by Na+ channels. Burst firing is thought to play an important role in the synchronized activity of the thalamus observed in absence epilepsy, but may also underlie a wider range of thalamocortical dysrhythmias. In addition to a pacemaker role, Ca2+ entry via T-type channels can directly regulate intracellular Ca2+ concentrations, which is an important second messenger for a variety of cellular processes. Molecular cloning revealed the existence of three T-type channel genes. The deduced amino acid sequence shows a similar four-repeat structure to that found in high-voltage-activated (HVA) Ca2+ channels, and Na+ channels, indicating that they are evolutionarily related. Hence, the α1-subunits of T-type channels are now designated Cav3. Although mRNAs for all three Cav3 subtypes are expressed in brain, they vary in terms of their peripheral expression, with Cav3.2 showing the widest expression. The electrophysiological activities of recombinant Cav3 channels are very similar to native T-type currents and can be differentiated from HVA channels by their activation at lower voltages, faster inactivation, slower deactivation, and smaller conductance of Ba2+. The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+. The goal of this review is to provide a comprehensive description of T-type currents, their distribution, regulation, pharmacology, and cloning.

show abstract

Class A Calcium Channel Variants in Pancreatic Islets and Their Role in Insulin Secretion

Cited by 81 publications

References 62 publications

Novel Cav2.1 Splice Variants Isolated from Purkinje Cells Do Not Generate P-type Ca2+ Current

Novel Cav2.1 Splice Variants Isolated from Purkinje Cells Do Not Generate P-type Ca2+ Current

Voltage-Gated Ion Channels in Human Pancreatic β-Cells: Electrophysiological Characterization and Role in Insulin Secretion

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

Contact Info

Product

Resources

About