- Brain Awareness Week
Protein phosphatase 2A in neuronal signal transduction
Reversible phosphorylation of key proteins, such as ion channels and neurotransmitter-synthesizing enzymes, regulates synaptic transmission and other aspects of neuronal physiology and development. While the enzymes that add phosphates to proteins, protein kinases, have been studied extensively, much less is known about the equally important enzymes that catalyze the reverse reaction, protein phosphatases
PP2A is one of the major classes of Ser/Thr phosphatases with likely thousands of phospho-protein substrates. The predominant form of PP2A is a heterotrimer of catalytic, scaffolding, and variable regulatory subunits. These variable subunits define substrate specificity, subcellular localization, and regulation of PP2A by second messengers and reversible phosphorylation. Our research focuses on two brain-specific PP2A regulatory subunits with relevance to neurodegenerative disorders, B'β and Bβ2. B'β acts as a gatekeeper in the regulation of tyrosine hydroxylase (TH) activity and catecholamine synthesis. Inhibitors of PP2A enzymes containing this subunit may therefore have therapeutic potential for Parkinson's disease. Bβ2 is derived from a gene mutated in spinocerebellar ataxia type 12 (SCA12) and recruits PP2A to the outer mitochondrial membrane to promote mitochondrial fission or inhibit mitochondrial fusion. Mitochondrial restructuring by Bβ2 sensitizes neurons to a variety of insults. Bβ2 inhibitors may thus form the basis for novel neuroprotective therapies. The kinase opposing PP2A/Ββ2's effect on mitochondrial morphology and survival is cAMP-dependent protein kinase (PKA) anchored to mitochondria via A kinase anchoring protein (AKAP) 1. We have thus far identified phosphorylation sites in two of the dynamin-family GTPases that sculpt mitochondria and are exploring their involvement in the morphogenetic and survival modulating activities of PP2A/Bβ2 and PKA/AKAP1.