In vivo regulation of Na/Ca exchanger expression by adrenergic effectors

Abstract

The Na/Ca exchanger encoded by the NCX1 gene plays an important role in calcium homeostasis in cardiac muscle. We previously identified three in vitro signaling pathways that are of major importance in the regulation of Na/Ca exchanger gene expression in neonatal cardiac myocytes, the protein kinase A (PKA) and protein kinase C (PKC) pathways, and intracellular Ca(2+). To determine whether these pathways are important in vivo, we stimulated the PKA and PKC pathways and examined functional expression of the Na/Ca exchanger in adult rat heart. After a 3- and 7-day treatment, norepinephrine (200 microg x kg(-1) x h(-1)), isoproterenol (150 microg x kg(-1) x h(-1)), and phenylephrine (200 microg x kg(-1) x h(-1)) each stimulated a significant increase in NCX1 mRNA levels (35-85%, P < 0.05). Norepinephrine also stimulated a 35% increase in protein abundance (P < 0.05), a 20% decrease in relaxation duration (P < 0.05), and a 25% reduction in the fluorescence decay constant (P < 0.05) after a 7-day treatment. We conclude that a 7-day treatment of alpha- and beta-adrenergic agonists increases the expression of functional Na/Ca exchangers in adult rat heart.

Calcium dynamics in the failing heart: restoration by β-adrenergic receptor blockade

“…SERCA, NCX, and L-type Ca 2ϩ channel current density levels were normalized by propranolol treatment, explaining the improved Ca 2ϩ handling in treated TOT mice. The shared normalization of SERCA, NCX, and L-type Ca 2ϩ channel by ␤-blockade in our heart failure model suggests that common regulatory pathways or Ca 2ϩ -handling proteins may exist downstream of ␤-receptors (14,16). SERCA and L-type Ca 2ϩ channel demonstrated enhanced restoration in protein content compared with NCX, suggesting that SERCA and L-type Ca 2ϩ channel regulation may be linked to ␤-adrenergic blockade given the short duration of treatment (16).…”

“…The shared normalization of SERCA, NCX, and L-type Ca 2ϩ channel by ␤-blockade in our heart failure model suggests that common regulatory pathways or Ca 2ϩ -handling proteins may exist downstream of ␤-receptors (14,16). SERCA and L-type Ca 2ϩ channel demonstrated enhanced restoration in protein content compared with NCX, suggesting that SERCA and L-type Ca 2ϩ channel regulation may be linked to ␤-adrenergic blockade given the short duration of treatment (16). These findings are in agreement with other studies that report improved SERCA and NCX levels after ␤-blockade in different heart failure models (19,28,47).…”

“…2D). Although ␤-adrenergic transcriptional regulation of SERCA, NCX, and L-type Ca 2ϩ channel remains obscure (11,14,16), our results indicate a dynamic interplay exists between ␤-blockade and reversal of maladaptive Ca 2ϩ -handling protein expression, as recently shown to occur in human dilated cardiomyopathy (31). Others (11,38) report that ␤-blockade stabilizes FK506 binding protein 12.6 binding to the RyR, resulting in reduced Ca 2ϩ channel leak and cytosolic Ca 2ϩ overload, attenuating heart failure.…”

Impaired Ca2+ Handling in Perfused Hypertrophic Hearts from Dahl Salt-Sensitive Rats

“…The mechanism regulating Ca 2 transporter gene expression is also unclear. Recently, Golden et al showed that α and β adrenergic agonists increased the expression of NCX1 mRNA in the adult rat heart (30). Changes in hormonal factors might affect gene expression in the progression from cardiac hypertrophy to failure.…”

Increased susceptibility to ventricular arrhythmias is associated with changes in Ca2+ regulatory proteins in paraplegic rats

“…Norepinephrine, the primary neurotransmitter of the sympathetic nervous system, mediates cardiac ionotropic, chronotropic, and lusitropic effects via multiple ionic mechanisms, including Ca 2ϩ homeostasis (49). Furthermore, adrenergic receptor activation alters the expression of genes that encode cardiac Ca 2ϩ regulatory proteins (13,29). The ability of cardiac myocytes to maintain cytosolic Ca 2ϩ concentration within a tightly controlled range is crucial for cardiac electrical stability (12).…”