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Paper text:
ampk is a heterotrimeric protein that consists of an  ,  and   subunit in equal stoichiometry .
the   subunit constitutes the catalytic domain , conferring kinase activity , while the   subunit enables ampk to monitor cellular energy status through two amp / atp binding domains , referred to as bateman domains , that bind amp or atp in a mutually exclusive manner .
the hydrolysis of atp , needed for driving thermodynamically unfavorable processes , results in the formation of adendosine monophosphate ( amp ) .
therefore , high concentrations of amp serve as a signal of increased energy expenditure and promote the binding of amp to the bateman domains .
amp binding causes ampk to undergo a conformational change , exposing an activation loop of the  subunit , allowing phosphorylation on threonine by upstream kinases , referred to as ampk kinases ( ampkks ) , resulting in a 50100-fold increase in the catalytic activity of ampk .
conversely , a high concentration of intracellular atp , characteristic of ample energy reserves , promotes atp / bateman domain binding and produces an antagonistic effect on ampk activation .
unlike other eukaryotic cell types , neurons must undergo a process of morphological polarization in order to function properly .
this process entails the selection and differentiation of multiple dendrites and an axon from a single cell body , which is required for neurons to send and receive information , providing the foundation for the function of neural networks .
neuronal polarization begins with the rapid extension of a single minor neurite into an axon of remarkable size and complex geometry , while the remaining sister neurites will eventually develop into dendrites .
the scale of biosynthesis required for axonal growth and thereby polarization , necessitates increased protein and membrane synthesis , in addition to the intracellular delivery of these building blocks to the growing axon tip .
considering the degree of atp consumption involved in axon formation , ampk is likely to be involved in the regulation of neuronal polarization .
our recent study has demonstrated that pharmacological activation of ampk , mimicking energy lacking conditions , during the transition from the symmetric stage 2 to the polarizing stage 3 , where the initial signals for axon specification are starting to occur , effectively inhibits axon specification and neuronal polarization in both cultured embryonic hippocampal neurons and embryonic cortical brain slices .
mechanistically , we show that direct phosphorylation of the kinesin light chain of the motor protein , kif5 , results in a dissociation between the motor complex and its pi3k cargo , thereby preventing pi3k enrichment at the neurite tip , a key mechanism in axon selection and growth ( fig .  1a and b ) .
importantly , expression of a kinase dead ampk mutant ( ampk kd ) can rescue polarity in cultured hippocampal neurons and cortical brain slices , regardless of aicar treatment , indicating that ampk upregulation , but not its basal activity , regulates neuron polarization ( fig . 
has shown that genetic knockout of both ampk 1/2 catalytic isoforms in mice had no effect on cortical neurogenesis or polarization . to indicate clinical significance
, we find that brief ischemia challenge during neuronal development causes phosphorylation of ampk and inhibition of neuronal polarization in cultured hippocampal neurons .
similarly , expression of ampk kd successfully rescued polarity in ischemia treated neurons , concluding that ischemia induced polarity inhibition is directly mediated by ampk .
( a ) under normal energy conditions ampk exists in an unphosphorylated / inactive state and pi3k is transported to the neurite tip via a physical association with the kif5 cargo adaptor , klc .
the accumulation of pi3k at a single neurite tip promotes the signaling responsible for axon initiation and growth .
( b ) under energy - lacking conditions , amp binds to ampk producing a conformational change in the kinase , allowing phospho - activation of ampk by upstream kinases ( ampkk ) .
ampk - caused klc phosphorylation dissociates pi3k , resulting in a loss of pi3k from the neurite tip and an inhibition of neuronal polarization .
control neuron shows typical single axon ( left ) , which is missing in a neuron treated with ampk activator aicar ( middle ) .
expression of kinase dead ( kd ) ampk rescues polarity in the aicar treated neuron .
is the fact that the serine / threonine kinase , lkb1 , the major upstream activator of ampk in peripheral cells , is required for successful polarization of neurons .
however , despite the fact that both lkb1 and ampk are expressed in nervous tissue , studies have indicated that lkb1 may not be the major regulator of ampk phosphorylation within the brain .
for example , under basal conditions , lkb1-deficient cortical neurons show no deficit in phosphorylated ampk when compared with wild - type cells , indicating an alternative means of ampk phosphorylation . however , it is possible that regulation of ampk by lkb1 is restricted to periods of energetic stress , when amp binding has exposed the activation loop of ampk .
it will be interesting to know whether ampk can be phosphorylated in lkb1-deficient neurons under atp - lacking conditions . in line with this ,
hawley et al . has shown that in rat brain slices , increases of intracellular calcium by membrane depolarization result in ampk phosphorylation .
phosphorylation of ampk was concluded to result from camkk activity , as the camkk inhibitor , sto-609 , abolished the effect .
importantly , membrane depolarization did not alter intracellular amp ratios , indicating that ampk can be regulated in a ca - dependent , amp - independent manner . considering that ca influx
is a hallmark of post - synaptic receptor activation , the ability of ampk to be phosphorylated by camkk may present a mechanism for coupling synaptic activity with energy regulation .
despite the ability of ampk to inhibit pi3k localization at the neurite tip , aicar treatment causes a marked increase in phosphorylated akt .
this effect results directly from ampk activation , as introduction of the ampk antagonist successfully blocks aicar - induced akt phosphorylation .
furthermore , addition of a pi3k inhibitor also abolishes aicar - induced akt phosphorylation , indicating that the ampk effect on akt activation is mediated via pi3k .
although the physiological role of ampk - dependent pi3k / akt activation remains to be investigated , we hypothesize that it may represent a mechanism for stimulating atp production .
specifically , ampk has previously been characterized as an upstream regulator of glucose uptake in neurons , a mechanism that involves increased translocation of the glucose transporter , glut3 , to the surface membrane .
similarly , insulin - like growth factor 1 ( igf1 ) has also been implicated in the regulation of glucose uptake in the brain and binds to receptor tyrosine kinases that associate with insulin receptor substrate ( irs-1 ) , a known upstream activator of the pi3k / akt signaling cascade .
interestingly , ampk has been observed to phosphorylate irs-1 , the most upstream component in the pi3k signaling pathway , in cell free assays and mouse myoblast c2c12 cell lines in response to aicar treatment , suggesting irs-1 as the intermediate factor linking ampk to pi3k / akt activation .
the ability of ampk to suppress neuronal polarization may have significant relevance within a clinical context .
since neuron polarization and appropriate axon extension are the necessary precondition for intercellular connection and communication , the disruption of neuronal polarity resulting from ampk activation should have long - lasting effects on synapse formation and ultimately , brain function .
we find that aicar treated neurons fail to specify an axon even after 3 d of recovery following treatment , indicating that the ampk effect on neuronal polarization may persist even after energy levels return to normal . in a similar scenario ,
pathological challenges occurring in early development , such as neonatal stroke and hypoxic - ischemic encephalopathy , that have been observed to promote ampk activation , also produce late - emergence cognitive deficits
. it will be interesting to know whether ampk signaling is indeed responsible for clinically observed neurological abnormalities related to neural energy deficiency during early development .
neuronal polarization , the process by which neurons form multiple dendrites and an axon from the soma , is the first critical step in the formation and function of neural networks . 
 polarization begins with the rapid extension of a single neurite to produce an axon of impressive size and complex geometry , while the remaining sister neurites differentiate into dendrites . 
 the extensive biosynthesis required to produce an axon therefore necessitates coordination with cellular energy status to ensure an ample energy supply . 
 our recent work shows that activity of the amp - activated protein kinase ( ampk ) , the bio - energy sensor responsible for maintaining cellular energy homeostasis in all eukaryotic cells , plays an important role in the initiation of axonal growth . 
 ampk phosphorylates the cargo - binding light chain of the kif5 motor protein , leading to dissociation of the phosphatidylinositol 3-kinase ( pi3k ) from the motor complex . 
 the mislocation of pi3k , which is normally enriched at the axonal tip for extension and differentiation , results in a lack of neurite specification and neuron polarization . 
 these findings reveal a link between cellular bioenergy homeostasis and neuron morphogenesis , and suggest a novel cellular mechanism underlying the long - term neurological abnormalities as a consequence of bioenergy deficiency during early brain development .