Table 1.
Neurological disorders in humans and mice involving IP3R1, calbindin (CB), parvalbumin (PV), and other calcium signaling proteins.
| Disorder | Mutant protein | IP3R1-associated | PV/CB | References | ||
|---|---|---|---|---|---|---|
| Expression | Sensitivity | Direct binding | Expression | |||
| SMOOTH ENDOPLASMIC RETICULUM CLUSTER | ||||||
| SCA1 | Ataxin-1 | Decreased | M | E | Decreased | Orr et al., 1993; Burright et al., 1995; Lin et al., 2000; Inoue et al., 2001; Liu et al., 2009 |
| SCA2 | Ataxin-2 | Decreased | Increased | E | Decreased | Pulst et al., 1996; Liu et al., 2009; Hansen et al., 2013 |
| SCA3 | Ataxin-3 | Decreased | Increased | E | M | Dürr et al., 1996; Paulson et al., 1997; Chen et al., 2008; Chou et al., 2008 |
| SCA7 | Ataxin-7 | Decreased | M | M | Decreased | David et al., 1997; Friedrich et al., 2012 |
| SCA8 | Ataxin-8 | M | M | M | M | Moseley et al., 2006; Krysa et al., 2012 |
| SCA17 | Ataxin-17 | M | M | M | M | Nakamura et al., 2001 |
| HD | Huntingtin | Decreased | Increased | E | M | Datta et al., 2011; Euler et al., 2012 |
| DLPRA | DLPRA | Decreased | M | E | Decreased | Liu et al., 2009; Suzuki et al., 2012 |
| SCA15 | IP3R1 | Decreased | U | U | U | van de Leemput et al., 2007; Hara et al., 2008; Di Gregorio et al., 2010 |
| SCA16 | IP3R1 | Decreased | U | U | U | Iwaki et al., 2008 |
| QG | CARP VIII | U* | M | E | U* | Hirota et al., 2003; Yan et al., 2007; Türkmen et al., 2009 |
| PLASMA MEMBRANE CLUSTER | ||||||
| A-HL | PMCA | Decreased | U | U | U | Kurnellas et al., 2007 |
| ARCCA | mGluR | U | U | U | U | Guergueltcheva et al., 2012 |
| EA2/leaner | Cav2.1 | U | U | U | Decreased | Guida et al., 2001; Murchison et al., 2002; Mantuano et al., 2004; Tonelli et al., 2006 |
| SCA6 | Cav2.1 | U | U | U | U | Ishikawa et al., 1997 |
| SCA14 | PKC-γ | U | U | U | U | Alonso et al., 2005; Shuvaev et al., 2011; van Gaalen et al., 2013; Ji et al., 2014 |
| SCA5 | Spectrin β | U | U | U | U | Ikeda et al., 2006 |
| EA6 | EAAT1 | U | U | U | U | de Vries et al., 2009 |
| EA5 | CavB4 | U | U | U | U | Escayg et al., 2000 |
| EA1 | Kv1.1 | U | U | U | U | Imbrici et al., 2006 |
| SCA13 | Kv3.3 | U | U | U | U | Waters et al., 2006 |
| SCA19 | Kv4.3 | U | U | U | U | Duarri et al., 2012 |
| SCA22 | Kv4.3 | U | U | U | U | Lee et al., 2012 |
SCA, spinocerebellar ataxia; HD, Huntington's disease; DLPRA, dentatorubral-pallidoluysian atrophy; leaner, mouse model corresponding to EA2; EA, episodic ataxia; QG, quadrupedal gait ataxia; ARCCA, autosomal-recessive congenital cerebellar ataxia. M, predicted by model; E, experimentally observed; U, Untested. U
, tested and unchanged in mouse model very early on at age 14 days, which may be too early to show changes, based on reduced inositol 1,4,5-trisphosphate receptor 1 (IP3R1) expression at age 26 days in the SCA2 mice (Hansen et al., 2013) (Supplemental Material, S4 IP3R1 suppression by CARP). ITPR1, intracellular calcium release channel on the endoplasmic reticulum gated by IP3; PKC-γ, kinase expressed in Purkinje neurons; CARP VIII, Carbonic anhydrase-related protein 8 (CA8), an IP3R1 antagonist (Türkmen et al., 2009); EAAT1, Excitatory amino-acid transporter type 1 (a glutamate transporter); Spectrin β, an excitatory amino-acid transporter type 1 (EAAT4; glutamate transporter) and GluRδ2 (Grid2, glutamate receptor) anchor; DAG, diacylglycerol a product of PLC hydrolysis that activates PKC along with calcium; PIP2, Phosphatidylinositol 4,5-bisphosphate, a plasma membrane phospholipid of the inner leaflet that gives rise to DAG and IP3 when hydrolyzed; PLC, phospholipase C, an enzyme that hydrolyzes PIP2 when activated by G-betagamma from mGluR; mGluR or Grm1, metabotropic glutamate receptor type 1; PMCA, Plasma membrane calcium ATP-ase transports calcium out of the cell; Cav2.1, main P-type calcium channel in PCs, with nonsense/missense mutations causing episodic ataxia type 2 and expansion of CAG repeats causing SCA6; CavB4, accessory subunit that regulates P-type channels encoded by Cav2.1; Kv1.1, Kv3.3, and Kv4.3 are potassium channels that contribute to repolarization of dendritic calcium spikes in Purkinje neurons; A-HL, ataxia and hearing loss in mice, hearing loss in humans. Adapted from Schorge et al. (2010).