Characterization of cDNA clones encoding two putative isoforms of the α<sub>1</sub> subunit of the dihydropyridine‐sensitive voltage‐dependent calcium channel isolated from rat brain and rat aorta

Koch, Walter J.; Hui, Anna; Shull, Gary E.; Ellinor, Patrick T.; Schwartz, Arnold

doi:10.1016/0014-5793(89)80761-6

Cited by 49 publications

(7 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Protein segments encoded by alternatively spliced exons are indicated by black or hatched boxes. Exons 1a, 1b, and 1c derive from three alternative promoters (15,42,45); exons 8a/8, 21/22, and 31/32 are spliced in a mutually exclusive manner (51,61,62,67); and exons 9*, 10*, 33, 45*, and 45 are alternative cassette exons (5,18,19,24,25). (B and C) RT-PCR assay of changes of exons 9* and 33 in embryonic mouse cortex from embryonic day 12 (E12) to day 18 (E18).…”

Section: Fig 1 (A)mentioning

confidence: 99%

Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins

Tang

Zheng

Nikolic

et al. 2009

Molecular and Cellular Biology

View full text Add to dashboard Cite

CaV1.2 voltage-gated calcium channels play critical roles in the control of membrane excitability, gene expression, and muscle contraction. These channels show diverse functional properties generated by alternative splicing at multiple sites within the CaV1.2 pre-mRNA. The molecular mechanisms controlling this splicing are not understood. We find that two exons in the CaV1.2 channel are controlled in part by members of the Fox family of splicing regulators. Exons 9* and 33 confer distinct electrophysiological properties on the channel and show opposite patterns of regulation during cortical development, with exon 9* progressively decreasing its inclusion in the CaV1. CaV1.2 L-type voltage-gated calcium channels are widely distributed in brain, heart, smooth muscle, and endocrine cells and play essential roles in gene expression, muscle contraction, and hormone release (6,13,16,39,47). These channels are composed of three subunits, with the ␣ 1 subunit being the largest and incorporating the conduction pore, the voltage sensor and gating apparatus, as well as sites for channel regulation by second messengers, drugs, and toxins (Fig. 1A) (9,14,17). This CaV1.2 subunit is subject to extensive alternative splicing that generates multiple functionally distinct isoforms (1,29,33,49,62). At least twenty of the 56 exons in the human CaV1.2 transcript are alternatively spliced (29,50,51,55). In particular, alternative exon 9* within the cytoplasmic I-II loop and exon 33 within the IVS3-IVS4 transmembrane segments confer different electrophysiological and pharmacological properties on the channel and exhibit tissue-specific differences in inclusion (30,31,54,55). Changes in exon 9* (also named exon 9A) splicing are seen in human arterial smooth muscle cells that have developed atherosclerosis (57) and in hypertrophied cardiomyocytes of spontaneously hypertensive rats (56). Alternative exons 9* and 33 are conserved across vertebrate species demonstrating their functional importance to the CaV1.2 channel. However, the molecular mechanisms controlling their splicing have not been studied.Members of the Fox protein family, homologs of the Feminizing on the X gene product from Caenorhabditis elegans (21,41,48), regulate the splicing of many neuron-and musclespecific splicing events (22,40,59,(63)(64)(65)(66). There are three mammalian family members, Fox1 (A2BP1), Fox2 (RBM9), and Fox3 (hnrbp3), each containing a nearly identical RNAbinding domain that recognizes the hexanucleotide element UGCAUG (2). These proteins bind the introns adjacent to their target exons where they generally repress splicing when bound upstream of the exon but enhance splicing from a downstream binding site (22,40,59,63,64,66). In addition to the RNA-binding domain, all three proteins have similar N and C-terminal domains that are extensively modified by alternative promoter use and alternative splicing to produce a large family of related proteins. Fox1 is expressed in neurons and muscle, and Fox3 is expressed only in neurons (22,23,36,59). Fox2 show...

show abstract

Section: Fig 1 (A)mentioning

confidence: 99%

Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins

Tang

Zheng

Nikolic

et al. 2009

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…Several laboratories are currently attempting to identify the specific binding sites on the a1 subunit (36). This should allow the development of drugs with high tissue specificity and favorable cardiac protective abilities.…”

Section: Calcium Channel Antagonistsmentioning

confidence: 99%

Mechanisms of Vasorelaxation

Dominiczak

Bohr

1992

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

The regulation of vascular resistance is critical to the maintenance of circulatory homeostasis. The primary regulator of this resistance is the level of contraction of vascular smooth muscle, which is determined by the balance of factors that cause contraction with those that cause relaxation of this muscle. This review will feature the latter. However, to do this in a meaningful manner, specific contractile factors will also be considered.Under physiological conditions, vascular smooth muscle (VSM) contraction requires a concentration of ionized calcium ([Ca2']J in the cytosol greater than M and an energy source, ATP. Normally, [Ca2+Ii is the regulated variable that determines the magnitude of contraction (VSM tone). Relaxation is effected by mechanisms represented in Fig. 1 that reduce [Ca2+Ii and are therefore relevant to this review. Two of the mechanisms utilize active pumps requiring energy from ATP to move calcium out of the cytosol against large concentration gradients. These are the ATPase of the calcium efflux pump in the plasma membrane and the ATPase that sequesters calcium into the sarcoplasmic reticulum (SR). The third calcium-lowering mechanism is the sodium

show abstract

“…Some of these differences can be attributed to speciesor tissue-specific variability (9), or existence ofdistinct genes (3,6,(10)(11)(12), or alternative splicing of a primary transcript (3,13). Ca2+ channels of other than L type share significant overall amino acid identity with the L-type channels, especially in membrane-spanning domains (14,15).…”

mentioning

confidence: 99%

Molecular diversity of L-type Ca2+ channel transcripts in human fibroblasts.

Soldatov

1992

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

View full text Add to dashboard Cite

The nucleotide sequence of cDNA encoing the human fibroblast Ca2+ channel of L type (HFCC) has been determined. It is highly homologous to L-type channels previously cloned from rabbit lung and heart as well as from rat brain. At least four sites of molecular diversity were identified in the nucleotide sequence of HFCC. Three of these include regions encoding the transmembrane segments IIS6, IIIS2, and IVS3, which are known to be important for channel gating properties. The positions of these sites correlate with RNA splice sites, indicating that the molecular diversity of the transcripts is a result of alternative splicing. The fourth diversity region is located at the C-terminal region and comprises insertions and deletions. It is suggested that these variations may give rise to multiple subforms of HFCC with altered electrophysiological properties.

show abstract

Characterization of cDNA clones encoding two putative isoforms of the α₁ subunit of the dihydropyridine‐sensitive voltage‐dependent calcium channel isolated from rat brain and rat aorta

Cited by 49 publications

References 15 publications

Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins

Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins

Mechanisms of Vasorelaxation

Molecular diversity of L-type Ca2+ channel transcripts in human fibroblasts.

Contact Info

Product

Resources

About

Characterization of cDNA clones encoding two putative isoforms of the α1 subunit of the dihydropyridine‐sensitive voltage‐dependent calcium channel isolated from rat brain and rat aorta

Cited by 49 publications

References 15 publications

Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins

Developmental Control of CaV1.2 L-Type Calcium Channel Splicing by Fox Proteins

Mechanisms of Vasorelaxation

Molecular diversity of L-type Ca2+ channel transcripts in human fibroblasts.

Contact Info

Product

Resources

About

Characterization of cDNA clones encoding two putative isoforms of the α₁ subunit of the dihydropyridine‐sensitive voltage‐dependent calcium channel isolated from rat brain and rat aorta