Left ventricular and aortic dysfunction in cystic fibrosis mice.

Background: Left ventricular (LV) abnormalities have been reported in cystic fibrosis (CF); however, it remains unclear if loss of cystic fibrosis transmembrane conductance regulator (CFTR) function causes heart defects independent of lung disease.

Methods: Using gut-corrected F508del CFTR mutant mice (ΔF508), which do not develop human lung disease, we examined in vivo heart and aortic function via 2D transthoracic echocardiography and LV catheterization.

Results: ΔF508 mouse hearts showed LV concentric remodeling along with enhanced inotropy (increased +dP/dt, fractional shortening, decreased isovolumetric contraction time) and greater lusitropy (-dP/dt, Tau).

MRP4 and CFTR in the regulation of cAMP and β-adrenergic contraction in cardiac myocytes.

Spatiotemporal regulation of cAMP in cardiac myocytes is integral to regulating the diverse functions downstream of β-adrenergic stimulation. The activities of cAMP phosphodiesterases modulate critical and well-studied cellular processes. Recently, in epithelial and smooth muscle cells, it was found that the multi-drug resistant protein 4 (MRP4) acts as a cAMP efflux pump to regulate intracellular cAMP levels and alter effector function, including activation of the cAMP-stimulated Cl(-) channel, CFTR (cystic fibrosis transmembrane conductance regulator).

Cardiomyocytes with disrupted CFTR function require CaMKII and Ca(2+)-activated Cl(-) channel activity to maintain contraction rate.

The physiological role of the cystic fibrosis transmembrane conductance regulator (CFTR) in cardiomyocytes remains unclear. Using spontaneously beating neonatal ventricular cardiomyocytes from wild-type (WT) or CFTR knockout (KO) mice, we examined the role of CFTR in the modulation of cardiomyocyte contraction rate. Contraction rates of spontaneously beating myocytes were captured by video imaging.

A small peptide inhibitor of the low voltage-activated calcium channel Cav3.1.

The calcium channel gamma(6) subunit modulates low voltage-activated (LVA) calcium current in both human embryonic kidney (HEK) cells and cardiomyocytes, although the mechanism of modulation is unknown. We recently showed that gamma(6) contains a critical GxxxA motif in the first transmembrane domain (TM1) that is essential for its inhibition of the Cav3.1 (LVA) calcium current.

A critical GxxxA motif in the gamma6 calcium channel subunit mediates its inhibitory effect on Cav3.1 calcium current.

The eight members of the calcium channel gamma subunit family are integral membrane proteins that regulate the expression and behaviour of voltage and ligand gated ion channels. While a subgroup consisting of gamma(2), gamma(3), gamma(4) and gamma(8) (the TARPs) modulate AMPA receptor localization and function, the gamma(1) and gamma(6) subunits conform to the original description of these proteins as regulators of voltage gated calcium channels. We have previously shown that the gamma(6) subunit is highly expressed in atrial myocytes and that it is capable of acting as a negative modulator of low voltage activated calcium current.

Calcium channel gamma subunits: a functionally diverse protein family.

The calcium channel gamma subunits comprise an eight-member protein family that share a common topology consisting of four transmembrane domains and intracellular N- and C-termini. Although the first gamma subunit was identified as an auxiliary subunit of a voltage-dependent calcium channel, a review of phylogenetic, bioinformatic, and functional studies indicates that they are a functionally diverse protein family. A cluster containing gamma1 and gamma6 conforms to the original description of the protein family as they seem to act primarily as subunits of calcium channels expressed in muscle.

Calcium channel gamma6 subunits are unique modulators of low voltage-activated (Cav3.1) calcium current.

The calcium channel gamma (gamma) subunit family consists of eight members whose functions include modulation of high voltage-activated (HVA) calcium currents in skeletal muscle and neurons, and regulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propanoic acid (AMPA) receptor targeting. Cardiac myocytes express at least three gamma subunits, gamma(4), gamma(6) and gamma(7), whose function(s) in the heart are unknown. Here we compare the effects of the previously uncharacterized gamma(6) subunit with that of gamma(4) and gamma(7) on a low voltage-activated calcium channel (Cav3.

Disruption of growth hormone secretion alters Ca2+ current density and expression of Ca2+ channel and insulin-like growth factor genes in rat atria.

The influence of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis on expression of low-voltage-activated (LVA) Ca2+ current in atrial tissue was investigated using spontaneous dwarf (SpDwf) rats, a mutant strain that lacks GH. Atrial myocytes from SpDwf rats express LVA and high-voltage-activated (HVA) Ca2+ currents and the Ca2+ channel alpha1-subunit genes CaV1.2, CaV2.

Distribution and relative expression levels of calcium channel beta subunits within the chambers of the rat heart.

Calcium channel beta subunits expressed in rat atria and atrial myocytes are identified and their expression quantified and compared to beta subunit expression in the ventricle. mRNAs encoding all four know beta subunits are expressed in atrial myocytes including the following splice variants: beta1a, beta2b, beta2c, beta2e and beta4d. The specific beta2 splice variants expressed in the atria (beta2b, beta2c, beta2e) differ from those previously reported from rat ventricle.

Molecular cloning of calcium channel alpha(2)delta-subunits from rat atria and the differential regulation of their expression by IGF-1.

Calcium channels are multimeric proteins consisting of pore-forming (alpha(1)) and auxiliary (alpha(2)delta, beta, gamma) subunits. The auxiliary alpha(2)delta-subunit regulates calcium current density and activation/inactivation kinetics when co-expressed with some, but not all, alpha(1)-subunits. Here we report the differential expression of three alpha(2)delta-subunit cDNAs in rat atria, atrial myocytes and ventricle, and demonstrate that IGF-1 selectively increases the expression of the alpha(2)delta-3 mRNA in the atria.

Identification of the calcium channel alpha 1E (Ca(v)2.3) isoform expressed in atrial myocytes.

Antisense oligonucleotides targeting the calcium channel alpha 1E (Ca(v)2.3) subunit significantly inhibit the insulin-like growth factor-1 (IGF-1)-stimulated increase in low voltage-activated (LVA) (T-type) calcium current in cultured rat atrial myocytes [Proc. Natl.

Quantitative analysis of the expression and distribution of calcium channel alpha 1 subunit mRNA in the atria and ventricles of the rat heart.

Two distinct calcium currents are present in mammalian cardiac myocytes. Utilizing quantitative RT-PCR methods, we have analysed the expression patterns and abundance of four calcium channel alpha 1 subunit mRNAs in different regions of the rat heart and compared them to the known density of calcium currents recorded from rat atria. Our results show that Ca(V)1.