The pathophysiology of psychiatric disorders and, in particular, the cellular and molecular mechanisms responsible for the maintenance of severe forms of psychiatric disorders such as depression and other mood disorders remains poorly understood. This is so despite evidence indicating that common pathways are involved in multiple psychological disorders. For example, compounds that target or affect the serotonin and/or norepinephrine receptor systems have been used to treat a variety of psychiatric disorders including, for example, depression, affective disorders, psychoses, and addiction. Nonetheless, little progress has been made to identify genes and gene products that may be suitable for use in gene therapy of psychiatric disorders.
The p11 gene product, also known as s100A10, is a member of the s100 protein family that exists as a heterotetramer in which a central p11 dimer anchors two annexin A2 chains (Lewit-Bentley et al., Cell. Biol. Int., 24: 799-802 (2000)). Northern blot analyses show that p11 expression, while ubiquitous, is low in liver, heart, and testes, moderate in brain, spleen, and thymus, and high in kidney, intestine, and lung (Saris et al., J. Biol. Chem., 262: 10663-10671 (1987)). Although p11 shares significant sequence homology with other members of the S100 family, several amino acid substitutions and deletions render it unique (Gerke et al., EMBO J., 4: 2917-2920 (1985); Glenney, J. Biol. Chem., 261: 7247-7252 (1986)). Like other S100 family proteins, p11 possesses two EF-hand loops, although differences in amino acid sequence apparently compromise the ability of p11's EF loops to bind calcium, resulting in a permanently activated state (Rety et al., Nat. Struct. Biol., 6: 89-95 (1999)). Cryo-electron microscopy studies show that the p11-annexinA2 heterotetramer fosters vesicle aggregation at the plasma membrane by forming symmetric junctions between opposing membrane surfaces (Lambert et al., J. Mol. Biol., 272: 42-55 (1997)). In this way, the p11-annexinA2 complex may also stabilize membrane proteins in a particular configuration.
Studies have identified interactions between p11 and membrane-resident proteins of neuronal cells, including serotonin receptor. The relationship of p11 and trafficking protein for membrane-bound proteins was first identified in yeast two-hybrid studies. In particular, the tetrodotoxin-resistant sodium channel, Nav 1.8, and the potassium channel, TWIK-related acid-sensitive K (TASK) 1, were identified as binding partners for p11, and their translocation to the plasma membrane was reliant upon the presence of a p11-annexinII complex (Girard et al., EMBO J., 21: 4439-4448 (2002); Okuse et al., Nature, 417: 653-656 (2002)). Further studies indicated that surface expression of these proteins were affected by levels of p11 (Poon et al., FEBS Lett., 558: 114-118 (2004)). The trafficking of three other membrane-resident proteins also has been linked to p11 expression, namely the epithelial Ca2+ channels TRPV5 and TRPV6, the acid-sensing ion channel ASIC1a, and the serotonin 1B receptor (Donier et al., J. Biol. Chem., 280: 38666-38672 (2005); Svenningsson et al., Science, 311: 77-80 (2006); van de Graaf et al., EMBO J., 22: 1478-1487 (2003)).
A recent report indicated that p11 overexpression increases surface expression of 5-HT1B, while p11 knockout mice demonstrate fewer binding sites for 5-HT1B receptor antagonists (Svenningsson et al., Science, 311: 77-80 (2006)). The report was not able to establish the role of p11 in depression-like states because of a number of confounding factors, some of which are associated with the study's use of transgenic mice. For example, the study could not distinguish between the developmental and physiological role of mice with a transgenically disrupted p11 gene. In another example, the study found that p11 overexpression in transgenic mice produced a generalized hyperactivity (Id. at 79).
Accordingly, there is a need for gene products that are useful in the treatment and understanding of psychiatric disorders, such as depression.
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USPTO Backgrounds