Diabetes-Induced Changes in the Alternative Splicing of the Slo Gene in Corporal Tissue

Kelvin Davies, Weixin Zhao, Moses T. Tar, Johanna C. Figueroa, Pratik Desai, Vytautas Verselis, Jack Kronengold, Hong Zhan Wang, Arnold Melman, George J. Christ

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Objectives: Erectile dysfunction is a common diabetic complication. Preclinical studies have documented that the Slo gene (encoding the BK or Maxi-K channel α-subunit) plays a critical role in erectile function. Therefore, we determined whether diabetes induces changes in the splicing of the Slo gene relevant to erectile function. Methods: Reverse transcriptase-polymerase chain reaction was used to compare Slo splice variant expression in corporal tissue excised from control and streptozotocin (STZ)-induced diabetic Fischer F-344 rats. Splice variants were sequenced, characterized by patch clamping, and fused to green fluorescent protein to determine cellular localization. The impact of altered Slo expression on erectile function was further evaluated in vivo. Results: A novel Slo splice variant (SVcyt, with a cytoplasmic location) was predominantly expressed in corporal tissue from control rats. STZ-diabetes caused upregulation of a channel-forming transcript SV0. Preliminary results suggest that SV0 was also more prevalent in the corporal tissue of human diabetic compared with nondiabetic patients. The change in isoform expression in STZ-treated rats was partially reversed by insulin treatment. Intracorporal injection of a plasmid expressing the SV0 transcript, but not SVcyt, restored erectile function in STZ-diabetic rats. Conclusions: Alternative splicing of the Slo transcript may represent an important compensatory mechanism to increase the ease with which relaxation of corporal tissue may be triggered as a result of a diabetes-related decline in erectile capacity.

Original languageEnglish (US)
Pages (from-to)1229-1237
Number of pages9
JournalEuropean Urology
Volume52
Issue number4
DOIs
StatePublished - Oct 2007

Fingerprint

Alternative Splicing
Streptozocin
Genes
Large-Conductance Calcium-Activated Potassium Channels
Experimental Diabetes Mellitus
Erectile Dysfunction
Diabetes Complications
Green Fluorescent Proteins
Reverse Transcriptase Polymerase Chain Reaction
Constriction
Protein Isoforms
Plasmids
Up-Regulation
Insulin
Injections
Therapeutics

Keywords

  • Diabetes
  • Erectile dysfunction
  • Maxi-K channel
  • Slo gene
  • Splicing

ASJC Scopus subject areas

  • Urology

Cite this

Diabetes-Induced Changes in the Alternative Splicing of the Slo Gene in Corporal Tissue. / Davies, Kelvin; Zhao, Weixin; Tar, Moses T.; Figueroa, Johanna C.; Desai, Pratik; Verselis, Vytautas; Kronengold, Jack; Wang, Hong Zhan; Melman, Arnold; Christ, George J.

In: European Urology, Vol. 52, No. 4, 10.2007, p. 1229-1237.

Research output: Contribution to journalArticle

Davies, K, Zhao, W, Tar, MT, Figueroa, JC, Desai, P, Verselis, V, Kronengold, J, Wang, HZ, Melman, A & Christ, GJ 2007, 'Diabetes-Induced Changes in the Alternative Splicing of the Slo Gene in Corporal Tissue', European Urology, vol. 52, no. 4, pp. 1229-1237. https://doi.org/10.1016/j.eururo.2006.11.028
Davies, Kelvin ; Zhao, Weixin ; Tar, Moses T. ; Figueroa, Johanna C. ; Desai, Pratik ; Verselis, Vytautas ; Kronengold, Jack ; Wang, Hong Zhan ; Melman, Arnold ; Christ, George J. / Diabetes-Induced Changes in the Alternative Splicing of the Slo Gene in Corporal Tissue. In: European Urology. 2007 ; Vol. 52, No. 4. pp. 1229-1237.
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AU - Davies, Kelvin

AU - Zhao, Weixin

AU - Tar, Moses T.

AU - Figueroa, Johanna C.

AU - Desai, Pratik

AU - Verselis, Vytautas

AU - Kronengold, Jack

AU - Wang, Hong Zhan

AU - Melman, Arnold

AU - Christ, George J.

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N2 - Objectives: Erectile dysfunction is a common diabetic complication. Preclinical studies have documented that the Slo gene (encoding the BK or Maxi-K channel α-subunit) plays a critical role in erectile function. Therefore, we determined whether diabetes induces changes in the splicing of the Slo gene relevant to erectile function. Methods: Reverse transcriptase-polymerase chain reaction was used to compare Slo splice variant expression in corporal tissue excised from control and streptozotocin (STZ)-induced diabetic Fischer F-344 rats. Splice variants were sequenced, characterized by patch clamping, and fused to green fluorescent protein to determine cellular localization. The impact of altered Slo expression on erectile function was further evaluated in vivo. Results: A novel Slo splice variant (SVcyt, with a cytoplasmic location) was predominantly expressed in corporal tissue from control rats. STZ-diabetes caused upregulation of a channel-forming transcript SV0. Preliminary results suggest that SV0 was also more prevalent in the corporal tissue of human diabetic compared with nondiabetic patients. The change in isoform expression in STZ-treated rats was partially reversed by insulin treatment. Intracorporal injection of a plasmid expressing the SV0 transcript, but not SVcyt, restored erectile function in STZ-diabetic rats. Conclusions: Alternative splicing of the Slo transcript may represent an important compensatory mechanism to increase the ease with which relaxation of corporal tissue may be triggered as a result of a diabetes-related decline in erectile capacity.

AB - Objectives: Erectile dysfunction is a common diabetic complication. Preclinical studies have documented that the Slo gene (encoding the BK or Maxi-K channel α-subunit) plays a critical role in erectile function. Therefore, we determined whether diabetes induces changes in the splicing of the Slo gene relevant to erectile function. Methods: Reverse transcriptase-polymerase chain reaction was used to compare Slo splice variant expression in corporal tissue excised from control and streptozotocin (STZ)-induced diabetic Fischer F-344 rats. Splice variants were sequenced, characterized by patch clamping, and fused to green fluorescent protein to determine cellular localization. The impact of altered Slo expression on erectile function was further evaluated in vivo. Results: A novel Slo splice variant (SVcyt, with a cytoplasmic location) was predominantly expressed in corporal tissue from control rats. STZ-diabetes caused upregulation of a channel-forming transcript SV0. Preliminary results suggest that SV0 was also more prevalent in the corporal tissue of human diabetic compared with nondiabetic patients. The change in isoform expression in STZ-treated rats was partially reversed by insulin treatment. Intracorporal injection of a plasmid expressing the SV0 transcript, but not SVcyt, restored erectile function in STZ-diabetic rats. Conclusions: Alternative splicing of the Slo transcript may represent an important compensatory mechanism to increase the ease with which relaxation of corporal tissue may be triggered as a result of a diabetes-related decline in erectile capacity.

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