Beneficial effects of adenylyl cyclase type 6 (AC6) expression persist using a catalytically inactive AC6 mutant

Mei Hua Gao, Tong Tang, Ngai Chin Lai, Atsushi Miyanohara, Tracy Guo, Rouying Tang, Amy L. Firth, Jason Yuan, H. Kirk Hammond

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Cardiac-directed expression of AC6 has pronounced favorable effects on cardiac function possibly not linked with cAMP production. To determine rigorously whether cAMP generation is required for the beneficial effects of increased AC6 expression, we generated a catalytically inactive AC6 mutant (AC6mut) that has markedly diminished cAMP generating capacity by replacing aspartic acid with alanine at position 426 in the C1 domain (catalytic region) of AC6. Gene transfer of AC6 or AC6mut (adenovirus-mediated) in adult rat cardiac myocytes resulted in similar expression levels and intracellular distribution, but AC6mut expression was associated with marked reduction in cAMP production. Despite marked reduction in cAMP generation, AC6mut influenced intracellular signaling events similarly to that observed after expression of catalytically intact AC6. For example, both AC6 and AC6mut reduced phenylephrine-induced cardiac myocyte hypertrophy and apoptosis (p < 0.001), expression of cardiac ankyrin repeat protein (p < 0.01), and phospholamban (p < 0.05). AC6mut expression, similar to its catalytically intact cohort, was associated with increased Ca2+ transients in cardiac myocytes after isoproterenol stimulation. Many of the biological effects of AC6 expression are replicated by a catalytically inactive AC6 mutant, indicating that the mechanisms for these effects do not require increased cAMP generation.

Original languageEnglish (US)
Pages (from-to)381-388
Number of pages8
JournalMolecular Pharmacology
Volume79
Issue number3
DOIs
StatePublished - Mar 2011
Externally publishedYes

Fingerprint

Cardiac Myocytes
Ankyrin Repeat
adenylyl cyclase 6
Cardiomegaly
Phenylephrine
Isoproterenol
Adenoviridae
Aspartic Acid
Alanine
Catalytic Domain
Apoptosis
Genes
Proteins

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Gao, M. H., Tang, T., Lai, N. C., Miyanohara, A., Guo, T., Tang, R., ... Hammond, H. K. (2011). Beneficial effects of adenylyl cyclase type 6 (AC6) expression persist using a catalytically inactive AC6 mutant. Molecular Pharmacology, 79(3), 381-388. https://doi.org/10.1124/mol.110.067298

Beneficial effects of adenylyl cyclase type 6 (AC6) expression persist using a catalytically inactive AC6 mutant. / Gao, Mei Hua; Tang, Tong; Lai, Ngai Chin; Miyanohara, Atsushi; Guo, Tracy; Tang, Rouying; Firth, Amy L.; Yuan, Jason; Hammond, H. Kirk.

In: Molecular Pharmacology, Vol. 79, No. 3, 03.2011, p. 381-388.

Research output: Contribution to journalArticle

Gao, MH, Tang, T, Lai, NC, Miyanohara, A, Guo, T, Tang, R, Firth, AL, Yuan, J & Hammond, HK 2011, 'Beneficial effects of adenylyl cyclase type 6 (AC6) expression persist using a catalytically inactive AC6 mutant', Molecular Pharmacology, vol. 79, no. 3, pp. 381-388. https://doi.org/10.1124/mol.110.067298
Gao, Mei Hua ; Tang, Tong ; Lai, Ngai Chin ; Miyanohara, Atsushi ; Guo, Tracy ; Tang, Rouying ; Firth, Amy L. ; Yuan, Jason ; Hammond, H. Kirk. / Beneficial effects of adenylyl cyclase type 6 (AC6) expression persist using a catalytically inactive AC6 mutant. In: Molecular Pharmacology. 2011 ; Vol. 79, No. 3. pp. 381-388.
@article{f6d067b0fa7a466b9cde73f8294b0fb3,
title = "Beneficial effects of adenylyl cyclase type 6 (AC6) expression persist using a catalytically inactive AC6 mutant",
abstract = "Cardiac-directed expression of AC6 has pronounced favorable effects on cardiac function possibly not linked with cAMP production. To determine rigorously whether cAMP generation is required for the beneficial effects of increased AC6 expression, we generated a catalytically inactive AC6 mutant (AC6mut) that has markedly diminished cAMP generating capacity by replacing aspartic acid with alanine at position 426 in the C1 domain (catalytic region) of AC6. Gene transfer of AC6 or AC6mut (adenovirus-mediated) in adult rat cardiac myocytes resulted in similar expression levels and intracellular distribution, but AC6mut expression was associated with marked reduction in cAMP production. Despite marked reduction in cAMP generation, AC6mut influenced intracellular signaling events similarly to that observed after expression of catalytically intact AC6. For example, both AC6 and AC6mut reduced phenylephrine-induced cardiac myocyte hypertrophy and apoptosis (p < 0.001), expression of cardiac ankyrin repeat protein (p < 0.01), and phospholamban (p < 0.05). AC6mut expression, similar to its catalytically intact cohort, was associated with increased Ca2+ transients in cardiac myocytes after isoproterenol stimulation. Many of the biological effects of AC6 expression are replicated by a catalytically inactive AC6 mutant, indicating that the mechanisms for these effects do not require increased cAMP generation.",
author = "Gao, {Mei Hua} and Tong Tang and Lai, {Ngai Chin} and Atsushi Miyanohara and Tracy Guo and Rouying Tang and Firth, {Amy L.} and Jason Yuan and Hammond, {H. Kirk}",
year = "2011",
month = "3",
doi = "10.1124/mol.110.067298",
language = "English (US)",
volume = "79",
pages = "381--388",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Beneficial effects of adenylyl cyclase type 6 (AC6) expression persist using a catalytically inactive AC6 mutant

AU - Gao, Mei Hua

AU - Tang, Tong

AU - Lai, Ngai Chin

AU - Miyanohara, Atsushi

AU - Guo, Tracy

AU - Tang, Rouying

AU - Firth, Amy L.

AU - Yuan, Jason

AU - Hammond, H. Kirk

PY - 2011/3

Y1 - 2011/3

N2 - Cardiac-directed expression of AC6 has pronounced favorable effects on cardiac function possibly not linked with cAMP production. To determine rigorously whether cAMP generation is required for the beneficial effects of increased AC6 expression, we generated a catalytically inactive AC6 mutant (AC6mut) that has markedly diminished cAMP generating capacity by replacing aspartic acid with alanine at position 426 in the C1 domain (catalytic region) of AC6. Gene transfer of AC6 or AC6mut (adenovirus-mediated) in adult rat cardiac myocytes resulted in similar expression levels and intracellular distribution, but AC6mut expression was associated with marked reduction in cAMP production. Despite marked reduction in cAMP generation, AC6mut influenced intracellular signaling events similarly to that observed after expression of catalytically intact AC6. For example, both AC6 and AC6mut reduced phenylephrine-induced cardiac myocyte hypertrophy and apoptosis (p < 0.001), expression of cardiac ankyrin repeat protein (p < 0.01), and phospholamban (p < 0.05). AC6mut expression, similar to its catalytically intact cohort, was associated with increased Ca2+ transients in cardiac myocytes after isoproterenol stimulation. Many of the biological effects of AC6 expression are replicated by a catalytically inactive AC6 mutant, indicating that the mechanisms for these effects do not require increased cAMP generation.

AB - Cardiac-directed expression of AC6 has pronounced favorable effects on cardiac function possibly not linked with cAMP production. To determine rigorously whether cAMP generation is required for the beneficial effects of increased AC6 expression, we generated a catalytically inactive AC6 mutant (AC6mut) that has markedly diminished cAMP generating capacity by replacing aspartic acid with alanine at position 426 in the C1 domain (catalytic region) of AC6. Gene transfer of AC6 or AC6mut (adenovirus-mediated) in adult rat cardiac myocytes resulted in similar expression levels and intracellular distribution, but AC6mut expression was associated with marked reduction in cAMP production. Despite marked reduction in cAMP generation, AC6mut influenced intracellular signaling events similarly to that observed after expression of catalytically intact AC6. For example, both AC6 and AC6mut reduced phenylephrine-induced cardiac myocyte hypertrophy and apoptosis (p < 0.001), expression of cardiac ankyrin repeat protein (p < 0.01), and phospholamban (p < 0.05). AC6mut expression, similar to its catalytically intact cohort, was associated with increased Ca2+ transients in cardiac myocytes after isoproterenol stimulation. Many of the biological effects of AC6 expression are replicated by a catalytically inactive AC6 mutant, indicating that the mechanisms for these effects do not require increased cAMP generation.

UR - http://www.scopus.com/inward/record.url?scp=79951967856&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79951967856&partnerID=8YFLogxK

U2 - 10.1124/mol.110.067298

DO - 10.1124/mol.110.067298

M3 - Article

C2 - 21127130

AN - SCOPUS:79951967856

VL - 79

SP - 381

EP - 388

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 3

ER -