Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling

Abstract

A persistent mystery about the ataxias has been why mutations in genes--many of which are expressed widely in the brain--primarily cause ataxia, and not, for example, epilepsy or dementia. Why should a polyglutamine stretch in the TATA-binding protein (that is important in all cells) particularly disrupt cerebellar coordination? We propose that advances in the genetics of cerebellar ataxias suggest a rational hypothesis for how so many different genes lead to predominantly cerebellar defects. We argue that the unifying feature of many genes involved in cerebellar ataxias is their impact on the signaling protein ITPR1 (inositiol 1,4,5-triphosphate receptor type 1), that underlies coincidence detection in Purkinje cells and could play an important role in cerebellar coordination.

Figure 1

The excitatory input to Purkinje cells (PCs). (a) PCs receive two fundamentally different forms of excitatory input. Parallel fibers (PF, red) arise from abundant granule cells in the cerebellum and provide many small inputs to PCs. Climbing fibers (CF, blue) arise from the inferior olive and each PC receives a single, powerful input from a CF. (b) Parallel fibers tend to activate metabotropic glutamate receptors, particularly mGluR1, that produces IP3 and activates endoplasmic reticulum (ER) IP3Rs (purple) encoded by ITPR1. Climbing fibers activate AMPA receptors (GluR, blue) that depolarize the cell enough to allow P-type calcium channels (P/Q) to open and allow calcium to enter the PC. Climbing fiber synapses are largely on the soma of PCs, for illustration purposes they are shown adjacent to PF synapses here.

Figure 2

ITPR1-dependent signaling in cerebellar PCs. (a) Cerebellar LTP. (i) Parallel fiber synapses activate mGluR1 (pink ball) in PC spines. (ii) mGluR1 activation triggers an increase in IP3. (iii) IP3 binds the IP3 receptor (encoded by ITPR1) on the ER within the PC spine, and leads to a local release of calcium from intracellular stores. (iv) Volleys of parallel fiber activation (in the absence of climbing fiber activation) lead to a steady, relatively low level calcium signal that binds to and activates protein phosphatases (PP). (v) Phosphatases, then dephosphorylate GluR2-containing AMPA receptors, and stabilize them in the membrane, leading to LTP of the active parallel fiber synapses. (b) Cerebellar LTD. (i) When a climbing fiber is stimulated it activates Ca²⁺-impermeable GluR2-containing AMPA receptors. (ii) Depolarization mediated by the activated GluR2-AMPA receptors opens voltage-gated P-type calcium channels CaV2.1. Individual climbing fiber activation leads to a long depolarization spread throughout the PC dendrites, and a calcium-dependent dendrite action potential. (iii) ITPR1 binds calcium that enters during the massive CF-mediated depolarization. Calcium works as an allosteric enhancer of IP3R gating. (iv) When IP3 produced by parallel fiber-mGluR1 activation binds to ITPR1 that is primed with bound-Ca²⁺ (from climbing fibers) ITPR1 produces a much larger (supra-linear) calcium signal. (v) The increased calcium is sufficient to activate PKC. (vi) Phosphorylation of GluR2 triggers internalization, leading to LTD.