Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing

Activated phosphatidylinositol 3 kinase/Protein kinase B (PI3K/AKT) signalling with increased or reduced mTOR and GSK3β activity influences the wound repair process. Diabetic wounds, usually ulcerated, are characterised by reduced growth factors and cellular performance. The occurrence of diabetic ulcers is linked to peripheral arterial disease, neuropathy, and wound contamination. Lasers or light emitting diodes (LEDs) provide photon energy with therapeutic benefits (Photobiomodulation-PBM), and has been broadly commended to quicken diabetic wound healing. PBM is efficient in the visible red and near-infrared electromagnetic spectrum, and fluencies ranging from 2 to 6 J/cm². However, cellular and molecular mechanisms induced by PBM are not fully understood. In this review we discuss PBM and the PI3K/AKT pathway with specific focus on the mTOR and GSK3β downstream activity in diabetic wound healing.     

Deletion of the C-terminal phosphorylation sites in the cardiac β-subunit does not affect the basic β-adrenergic response of the heart and the Ca(v)1.2 channel

Phosphorylation of the cardiac β subunit (Ca(v)β(2)) of the Ca(v)1.2 L-type Ca(2+) channel complex has been proposed as a mechanism for regulation of L-type Ca(2+) channels by various protein kinases including PKA, CaMKII, Akt/PKB, and PKG. To test this hypothesis directly in vivo, we generated a knock-in mouse line with targeted mutation of the Ca(v)β(2) gene by insertion of a stop codon after proline 501 in exon 14 (mouse sequence Cacnb2; βStop mouse). This mutation prevented translation of the Ca(v)β(2) C terminus that contains the relevant phosphorylation sites for the above protein kinases. Homozygous cardiac βStop mice were born at Mendelian ratio, had a normal life expectancy, and normal basal L-type I(Ca). The regulation of the L-type current by stimulation of the β-adrenergic receptor was unaffected in vivo and in cardiomyocytes (CMs). βStop mice were cross-bred with mice expressing the Ca(v)1.2 gene containing the mutation S1928A (SAβStop) or S1512A and S1570A (SFβStop) in the C terminus of the α(1C) subunit. The β-adrenergic regulation of the cardiac I(Ca) was unaltered in these mouse lines. In contrast, truncation of the Ca(v)1.2 at Asp(1904) abolished β-adrenergic up-regulation of I(Ca) in murine embryonic CMs. We conclude that phosphorylation of the C-terminal sites in Ca(v)β(2), Ser(1928), Ser(1512), and Ser(1570) of the Ca(v)1.2 protein is functionally not involved in the adrenergic regulation of the murine cardiac Ca(v)1.2 channel.