Neuron membrane trafficking and protein kinases involved in autism and ADHD

Abstract

A brain-enriched multi-domain scaffolding protein, neurobeachin has been identified as a candidate gene for autism patients. Mutations in the synaptic adhesion protein cell adhesion molecule 1 (CADM1) are also associated with autism spectrum disorder, a neurodevelopmental disorder of uncertain molecular origin. Potential roles of neurobeachin and CADM1 have been suggested to a function of vesicle transport in endosomal trafficking. It seems that protein kinase B (AKT) and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) have key roles in the neuron membrane trafficking involved in the pathogenesis of autism. Attention deficit hyperactivity disorder (ADHD) is documented to dopaminergic insufficiencies, which is attributed to synaptic dysfunction of dopamine transporter (DAT). AKT is also essential for the DAT cell-surface redistribution. In the present paper, we summarize and discuss the importance of several protein kinases that regulate the membrane trafficking involved in autism and ADHD, suggesting new targets for therapeutic intervention.

Figure 1

Schematic diagram representing the primary domain structures of neurobeachin (NBEA) and cell adhesion molecule 1 (CADM1) proteins. The functionally important sites are depicted. Note that the sizes of the proteins are modified for clarity. ARM, armadillo-typed domain; ConA, concanavalin A; AKAP, A-kinase anchor protein; PH, pleckstrin homology; BEACH, Beige and Chediak-Higashi domain; WD40, β-transducin repeat domain; V, variable-set Ig domain; C2, C2-set Ig domain; TM, transmembrane domain.

Figure 2

Schematic illustration of intracellular dopamine transporter (DAT) signaling with PKA and AKT pathways has been shown. Arrowhead means stimulation whereas hammerhead represents inhibition. Note that some critical pathways have been omitted for clarity.

Figure 3

Schematic depiction and overview of PI3K/AKT/PTEN signaling has been shown. Example molecules known to act on the PI3K/AKT/PTEN pathway are also shown. Arrowhead means stimulation whereas hammerhead represents inhibition. Note that some critical pathways have been omitted for clarity.

Figure 4

Schematic implication of protein kinases PKA and AKT modulation in the pathogenesis of autisms and ADHD. Alteration of the functions in neurobeachin, CADM1 and DAT with genetic deletion and/or single nucleotide polymorphisms (SNPs) may change the activity or selectivity of kinase to substrates, which in turn may cause the psychological disorders. Star faces represent an image of the individual kinase activities. Sad faces mean unbalance of kinase activity.

Figure 5

The balance of PKA and AKT kinases in the meaning of their functions may be important for normal neuronal development and individual psychiatric health. Several food and/or dietary components may contribute to the improved balance of the AKT and PKA signaling via the modulation of kinase activities. Star faces represent an image of the individual kinase activities. Smiled faces mean appropriate balance of kinase activity.