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Insulin binding to the insulin receptor, IR, a receptor tyrosine kinase consisting of a tetramer of

extracellular -subunits and intracellular -subunits activates -subunit kinase activity and
transphosphorylation leading to phosphorylation of the insulin receptor substrate protein IRS-1
IRS proteins are characteri!ed by pleckstrin-homology and phosphotyrosine-binding domains
that enable the binding of IRS-1 to "I#-$, a dimer of catalytic and regulatory subunits %he IRS-
1&"I#-$ interaction generates phosphatidylinositol-#,',(-triphosphate )"I"#*, leading to
activation of +kt,protein kinase - via the #-phosphoinositide&dependent protein kinase 1
)".$1* +kt,protein kinase - inhibits the Rab-/%"ase&activating protein +S101, resulting in
activation of Rab small /%"ases re2uired for translocation of /34%' from /34%' storage
vesicles )/S5s* enriched in IR+" and the vesicle-associated S6+R7 protein 5+8"-9 .ocking
and fusion of /S5s :ith the plasma membrane is regulated by insulin /34%' and 6a,$-
+%"ase do not co-locali!e to the same skeletal muscle intracellular membrane vesicles
Insulin increases 6a,$-+%"ase activity and plasma membrane expression through a "I#-$,
atypical protein kinase ; )a"$;*, and 7R$1,9 mitogen-activated protein kinase path:ay,
although the path:ay is less :ell defined
7R$1,9 activation occurs through a"$; in a 87$1,9 kinase&dependent manner 7R$1,9 kinase
phosphorylation of the 6a,$-+%"ase -subunit promotes membrane expression and translocation
of 6a,$-+%"ase from an intracellular membrane pool to the sarcolemma possibly in part by
retarding clathrin-dependent endocytosis
%he regulatory protein <=>.1, or phospholemman, belongs to a family of proteins characteri!ed
by an <=>. se2uence that associates :ith 6a,$-+%"ase and modulates its affinities for 6a
or its Imax
<=>.1 suppresses 6a,$-+%"ase activity by reducing its 6a
affinity or altering its Imax
"hosphorylation of <=>.1 by protein kinase + or protein kinase ; modifies its interaction :ith