Adenylyl Cyclase Type 6 Deletion Decreases Left Ventricular Function via Impaired Calcium Handling

Tang, Tong; Gao, Mei Hua; Lai, N. Chin; Firth, Amy L.; Takahashi, Toshiyuki; Guo, Tracy; Yuan, Jason X.‐J.; Roth, David M.; Hammond, H. Kirk

doi:10.1161/circulationaha.107.730069

Cited by 100 publications

(123 citation statements)

References 27 publications

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“…1A, lane 3), indicating that the AC5/6 antibody favorably cross-reacts with the AC6 protein alone. A recent study (27) also showed that the commercial antibody failed to detect AC5 protein in the AC6 KO hearts, further corroborating our results.…”

Section: Discussionsupporting

confidence: 92%

Adenylyl cyclase type 5 protein expression during cardiac development and stress

Hu¹,

Chandra²,

Ge³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Adenylyl cyclase (AC) types 5 and 6 (AC5 and AC6) are the two major AC isoforms expressed in the mammalian heart that mediate signals from ␤-adrenergic receptor stimulation. Because of the unavailability of isoform-specific antibodies, it is difficult to ascertain the expression levels of AC5 protein in the heart. Here we demonstrated the successful generation of an AC5 isoform-specific mouse monoclonal antibody and studied the expression of AC5 protein during cardiac development in different mammalian species. The specificity of the antibody was confirmed using heart and brain tissues from AC5 knockout mice and from transgenic mice overexpressing AC5. In mice, the AC5 protein was highest in the brain but was also detectable in all organs studied, including the heart, brain, lung, liver, stomach, kidney, skeletal muscle, and vascular tissues. Western blot analysis showed that AC5 was most abundant in the neonatal heart and declined to basal levels in the adult heart. AC5 protein increased in the heart with pressure-overload left ventricular hypertrophy. Thus this new AC5 antibody demonstrated that this AC isoform behaves similarly to fetal type genes, such as atrial natriuretic peptide; i.e., it declines with development and increases with pressureoverload hypertrophy. adenylyl cyclase isoforms; monoclonal antibody; pressure overload; hypertrophy ADENYLYL CYCLASE (AC) is an enzyme that catalyzes the conversion of ATP to cAMP. The complexity in understanding the signaling pathway of cAMP can be attributed, in part, to 10 isoforms of AC: nine membrane bound and one soluble, which have been cloned and characterized in mammals (4,6,9,10,29). Each of these membrane-bound isoforms consists of two hydrophobic domains (with 6 transmembrane spans) and two cytoplasmic domains. The cytoplasmic domains constitute the catalytic site, which is subject to intracellular regulation (6). The AC isoforms have high amino acid homology in their cytoplasmic domains but differ in the sequence of the transmembrane region. The specificity of tissue distribution, the functional properties, and the chromosomal location of the corresponding genes also differentiate these isoforms (4, 10, 12). The major AC isoforms expressed in the heart are type 5 (AC5) and type 6 (AC6) (7,11,30). Tissue distribution and developmental expression of AC5 and AC6 mRNA have been previously studied in rats, chicks, and humans (7,30,31). However, in the absence of an AC5-specific antibody, it has not been possible to determine the levels of protein expression. It is very important to study the differential regulation of AC5 and AC6 in the heart since AC5 and AC6 behave differently in the pathogenesis of heart failure. We demonstrated that the AC5 knockout (KO) mouse model lives longer and is resistant to stress (32), including chronic pressure overload (21) and chronic catecholamine (22) stress. However, studies by others have suggested that the overexpression of AC6 is beneficial and might be considered for heart failure therapy (23). In addition, based on mRNA...

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Section: Discussionsupporting

confidence: 92%

Adenylyl cyclase type 5 protein expression during cardiac development and stress

Hu¹,

Chandra²,

Ge³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…AC6 -/-mice were described previously (50), and WT littermates were used as controls. A conditional mouse model with AC6 constitutively deleted specifically in CNT cells and CD PCs (termed AC6 loxloxCre mice) was generated by breeding transgenic mice in which exons 3-12 of the Adcy6 gene were flanked by loxP sites (termed AC6 loxlox , ref.…”

Section: Methodsmentioning

confidence: 99%

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

Poulsen¹,

Kristensen²,

Brooks³

et al. 2017

JCI Insight

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“…Age-matched adult male and female AC6 2/2 and WT littermates were generated as described 53 using heterozygous breeding; their genetic background is a mix of 129Sv/J and C57BL/6. Mice were fed either a control diet (0.6% P i , 0.8% Ca 2+ ; Harlan Teklad, Madison, WI) or for studying the effect of P i intake, a zero P i diet (0% P i , 0.8% Ca 2+ ; Harlan Teklad).…”

Section: Concise Methodsmentioning

confidence: 99%

Renal Phosphate Wasting in the Absence of Adenylyl Cyclase 6

Fenton

Murray

Rieg

et al. 2014

Journal of the American Society of Nephrology

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Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) enhance phosphate excretion by the proximal tubule of the kidney by retrieval of the sodium-dependent phosphate transporters (Npt2a and Npt2c) from the apical plasma membrane. PTH activates adenylyl cyclase (AC) through PTH 1 receptors and stimulates the cAMP/PKA signaling pathway. However, the precise role and isoform(s) of AC in phosphate homeostasis are not known. We report here that mice lacking AC6 (AC6 2/2 ) have increased plasma PTH and FGF-23 levels compared with wild-type (WT) mice but comparable plasma phosphate concentrations. Acute activation of the calcium-sensing receptor or feeding a zero phosphate diet almost completely suppressed plasma PTH levels in both AC6 2/2 and WT mice, indicating a secondary cause for hyperparathyroidism. Pharmacologic blockade of FGF receptors resulted in a comparable increase in plasma phosphate between genotypes, whereas urinary phosphate remained significantly higher in AC6 2/2 mice. Compared with WT mice, AC6 2/2 mice had reduced renal Npt2a and Npt2c protein abundance, with approximately 80% of Npt2a residing in lysosomes. WT mice responded to exogenous PTH with redistribution of Npt2a from proximal tubule microvilli to intracellular compartments and lysosomes alongside a PTH-induced dose-response relationship for fractional phosphate excretion and urinary cAMP excretion. These responses were absent in AC6 2/2 mice. In conclusion, AC6 in the proximal tubule modulates cAMP formation, Npt2a trafficking, and urinary phosphate excretion, which are highlighted by renal phosphate wasting in AC6 2/2 mice. 25: 282225: -283425: , 201425: . doi: 10.1681 Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) are the primary regulators of renal phosphate (P i ) excretion by the proximal tubule and critically involved in the regulation of P i balance and maintenance of plasma P i . PTH acts on the proximal tubule through the G s protein-coupled PTH 1 receptor (PTH 1 R) to stimulate adenylyl cyclase (AC) and, thus, the synthesis of cAMP and consecutive activation of protein kinase A (PKA). 1-3 After activation of PTH 1 R, the sodiumphosphate cotransporters Npt2a and Npt2c (approximately 70% and approximately 30% reabsorption of filtered P i , respectively) are retrieved from the apical plasma membrane, resulting in increased P i excretion. [4][5][6] In addition, cAMP-independent effects of PTH have been reported, 7 which may involve PTH 1 R action on phosphoinositide-specific phospholipase C (PLC) 8,9 and mitogen-activated protein kinases. 10,11 FGF-23 mediates its action in the proximal tubule through the FGF receptor/Klotho complex, which downregulates the expression of Npt2a and Npt2c. 12,13 Immunohistochemistry J Am Soc Nephrol

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Adenylyl Cyclase Type 6 Deletion Decreases Left Ventricular Function via Impaired Calcium Handling

Cited by 100 publications

References 27 publications

Adenylyl cyclase type 5 protein expression during cardiac development and stress

Adenylyl cyclase type 5 protein expression during cardiac development and stress

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

Renal Phosphate Wasting in the Absence of Adenylyl Cyclase 6

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