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y the intracellular AMP ATP ratio, but also by phosphorylation at Thr by AMPK kinases . Lately two AMPKK's have been identified, namely LKB and CaMKK . In the heart, AMPK can be activated for the duration of physical exercise, hypoxia and ischemia . The main downstream target of AMPK is acetyl CoA carboxylase . Active AMPK phosphorylates Ubiquitin conjugation inhibitor ACC at Ser thereby inactivating ACC which results in an increase in LCFA oxidation. AMPK is a protein consisting of three various subunits, the catalytic subunit along with the regulatory and γ subunits. Although two isoforms with the catalytic subunit are present in the heart, the subunit is predominant . Lately, it was shown that in heart from transgenic mice overexpressing a dominant negative AMPK mutant, contraction was nonetheless able to stimulate glucose uptake .
This demonstrates that contraction induced glucose uptake can only be partly ascribed to AMPK. Interestingly, in H K skeletal muscle cells expressing dominant negative AMPK , Ubiquitin conjugation inhibitor a cellpermeable diacylglycerol analogue, phorbol myristate acetate , was able to stimulate glucose uptake , suggesting that a protein kinase sensitive to DAG is involved. In L skeletal muscle cells it has been demonstrated that the DAG sensitive protein kinase D directly contributes to basal glucose uptake . Taken with each other, these results suggest that PKD, along with AMPK, could also mediate contraction induced glucose Docetaxel uptake. Previously, PKD has been classified as a member with the PKC family members , and has been frequently referred to as PKC . The PKC family members consists of three subfamilies, i.e conventional, novel and atypical PKCs .
Standard PKCs require diacylglycerol and Ca for their activation, whereas novel PKCs VEGF also require DAG but are Ca independent, and atypical PKC's require neither DAG nor calcium . PKD possesses a DAG binding web-site, and was for that reason subclassified Docetaxel as a novel PKC isoform, i.e PKC . However, the catalytic domain of PKD is far more closely related to that with the Ca calmodulin regulated protein kinases and displays relatively little homology to the catalytic domains with the PKC family members . Moreover, in comparison to other members with the PKC family members, PKD possesses an added pleckstrin homology domain, a putative transmembrane sequence and lacks a pseudosubstrate region.
Consequently, PKD has been positioned into a novel kinase family members, comprising three members: PKD , PKD and PKD In non stimulated mammalian cell lines, PKD was identified to be localized to the cytosol and several intracellular membrane compartments such as Golgi and mitochondria . Therapy of COS cells with phorbol esters Conjugating enzyme inhibitor induced a persistent translocation of PKD from the cytosol to the plasma membrane, requiring the DAG binding domain. Along with phorbol esters, PKD may also be activated by different agonists, most of which bind to G protein coupled receptors . GPCR mediated activation of PKD is mediated by members with the PKC family members, and entails a phosphorylation of two serine residues within the activation loop, i.e Ser and Ser . Along with the transphosphorylation at Ser , PKD is autophosphorylated at Ser upon activation . Ser autophosphorylation has also been shown to happen upon phorbol ester stimulation, and was identified to correlate accurately with catalytic activity of PKD .
PKD has been identified to be present in the heart, where it is also activated by phorbol ester treatment . Additionally, GPCRs have been shown Docetaxel to activate PKD in the heart through a PKC dependent mechanism . The heart expresses several conventional and novel PKC isoforms . It has not yet been investigated which of these PKCs is involved in GPCR mediated PKD activation. In the present study, we explored in cardiac myocytes whether or not PKD is activated by contraction, and whether or not this is linked to glucose uptake. 1st, we determined whether or not electrically induced contraction and treatment of cardiac myocytes with oligomycin stimulated PKD translocation, Ser phosphorylation, also as PKD enzymatic activity.
Subsequently, the positioning of PKD relative to AMPK was studied with in vitro kinase assays Docetaxel and in cardiac myocytes isolated from AMPK ? ? mice. Thereafter, we attempted to determine upstream kinases involved in oligomycin contractioninduced PKD activation in cardiac myocytes. Lastly, we linked contraction induced PKD activation to contraction induced glucose uptake by using pharmacological agents that inhibit selected PKCs also as PKD. The combined observations reveal that PKD is activated in cardiac myocytes by contraction, independent of AMPK activation. This suggests that there is a PKD mediated contraction signaling pathway leading to GLUT translocation, parallel to AMPK signaling. Autophosphorylation of PKD at Ser is viewed as to be an accurate indicator of activity of this protein kinase . We initial determined the optimal circumstances for oligomycin treatment of cardiac myocytes . Therapy of cardiac myocytes with oligomycin at M already improved Ser phosphorylation by . fold, which slightly improved to . fold abo