Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms.

Abbreviations: ACC s acetyl-CoA carboxylase; AMP-PK s protein serinerthreonine kinase activated by 5-AMP; CPT-I s carnitine palmitoyltransferase-I; CREB protein s cyclic AMP-response element binding protein; ERKs s extracellular signal-regulated kinases: the MAP kinases originally Ž identified are now known to represent a sub-set of a wider family; the original members of the family are now referred to as ‘ERKs’ extracellular . Ž . signal-regulated kinase ; other sub-types of MAP kinases are JNKs c-Jun, N-terminal kinases and p38rRK; p125-FAK s 125-kDa focal adhesion Ž . protein tyrosine kinase; Grb s growth-factor-receptor bound protein; GSK-3 s glycogen synthase kinase-3; HDL s high-density lipoprotein; Ž . Ž . IRS-1 -2 s insulin receptor substrate-1 -2 ; HSP s heat shock protein; MAP kinase s initially named for an insulin-stimulated protein SerrThr kinase Ž . able to phosphorylate microtubule-associated protein-2 MAP-2 ; also commonly referred to as ‘mitogen-activated protein kinase’; MAPKAP-kinase s MAP-kinase-activated protein kinase: MAPKAP-K1 is identical to p90rsk, MAPKAP-K2 is distinct and activated downstream from p38rRK; MEKs s Ž dual-specificity MAP kinaseor ERK-kinases able to phosphorylate the TEY motif of the MAP kinasesrERKs; MEKKs s protein kinases able to Ž . phosphorylate and activate MEKs; other mammalian protein kinases which can fulfil this function include the c-Raf family and c-Mos; PDC PDC-P s Ž . pyruvate dehydrogenase complex and the inactive phosphorylated form ; PDE-III s cyclic nucleotide phosphodiesterase, ‘low K , particulate’ isoform m which is inhibitable by cyclic GMP; PKA s cyclic-AMP-dependent protein kinase; PKB s protein kinase B, also identified as the proto-oncogene akt Ž . and as RAC protein kinase Related to A or C kinase ; PKC s protein kinase C; PHAS s 22-kDa, phosphorylated, heatand acid-stable protein; able Ž . to bind to the eukaryotic initiation factor 4, ‘cap-binding’ complex, therefore also designated as eIF-4E:Bp eukaryotic initiation factor-4E binding protein ; Ž PI-3-kinase s phosphatidylinositol-3-OH-kinase comprised of ‘p85’ and ‘p110’ subunits which are respectively the 85-kDa regulatory, SH2-containing . and 110-kDa catalytic subunits ; PTB domain s phosphotyrosine binding domain, equivalent in function to SH2 domains but with distinct structure and target-binding characteristics; p21-Ras s 21-kDa GTPase encoded by cellular homologue of rat sarcoma oncogene; Ras-GAP s GTPase-activating protein for p21-Ras; p90rsk s 90-kDa isoform of ribosomal protein S6 kinase; distinct from p70 S6K, the 70-kDar85-kDa family of ribosomal S6 protein kinases; since p90-rsk is phosphorylated and activated by MAP kinases, it is also recognized as MAPKAP kinase-1; SH2 and SH3 domains s Ž src-homology domains 2 and 3 sequences related to non-catalytic domains of the protein tyrosine kinase pp60src and which function by binding, . respectively, to phosphotyrosine motifs and proline-rich domains of target proteins .; Shc s adaptor protein with homologies to Src and to collagen; Sos Ž . Ž s guanine nucleotide exchange factor GDP-release factor for p21-Ras, designated ‘son-of-sevenless’ and named from a Drosophila mutant manifest in . development of cell designated ‘R-seven’ due to a defect in signalling downstream from the ‘sev’ receptor tyrosine kinase; STAT s signal transducer and activator of transcription – transcription factors which have SH2 and tyrosyl-phosphorylation domains for dimerization to facilitate translocation from Ž . TCF cytosol to nucleus upon cytokine or hormone activation; STZ s streptozotocin; Syp s SH2-containing protein tyrosine phosphatase SH-PTP2 ; p60 Ž . Ž . s 60-kDa ‘ternary complex factor’, also designated Elk-1; TOR mTOR s target of rapamycin, first defined in yeast and mammalian homologue ; VAMP s vesicle-associated membrane protein; VLDL s very low density lipoprotein