Disruption of Growth Hormone Secretion Alters Calcium Current Density and the Expression of Calcium Channel and Insulin-Like Growth Factor Genes in Rat Atria

The influence of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis on the expression of low voltage-activated (LVA) calcium 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 HVA calcium currents and the calcium channel alpha-1 subunit genes, CaV1.2, CaV2.3, CaV3.1, and CaV3.2. LVA current density decreases significantly beginning at, or shortly after, birth in normal animals; however, its density is maintained in SpDwf rats at 1pA/pF for at least 12 weeks after birth. The abundance of mRNAs encoding CaV2.3 and CaV3.2 decline with advancing age in normal atrial development, yet the expression of CaV2.3 mRNA remains significantly elevated in older SpDwf animals. Quantitation of local transcript levels for mRNAs encoding IGF-1 and IGF-1 receptor also reveals significant differences in the expression of these transcripts in atrial tissue of SpDwf animals as compared to controls. In the SpDwf rats, the abundance of IGF-1 receptor mRNA remains elevated at many postnatal ages while mRNA encoding IGF-1 is maintained only in older animals. Physiological concentrations of IGF-1 cause 2to 3-fold increase in LVA current density in primary cultures of atrial myocytes and this effect is blocked by an antisense oligonucleotide targeting the IGF-1 receptor. Thus, disruption of GH production in SpDwf animals alters the expression of both atrial LVA calcium channel and IGF genes as well as the postnatal regulation of LVA calcium current density, most likely acting through compensatory mechanisms via the local IGF-1 receptor.