Schizophrenia Research Forum - A Catalyst for Creative Thinking

Researchers Retract Calcyon-D1 Receptor Link

5 January 2007. So short a phrase and yet so hard to say: "We made a mistake." But the researchers who initially reported that the protein calcyon complexes with the dopamine D1 receptor, thereby facilitating intracellular calcium increases, have been brave enough to say just this. According to their retraction in the December 15, 2006, issue of Science, calcyon and D1 do not directly interact after all.

In their original publication, the team led by Clare Bergson and Nelson Lezcano of the Medical College of Georgia reported finding a new protein, dubbed calcyon, in interaction screens of the D1 receptor. They also reported that stimulation of the D1 receptor, in tandem with stimulation of G-protein coupled receptors, boosted intracellular Ca2+ (Lezcano et al., 2000). These findings remain true; however, the finding that calcyon forms a complex with D1, and that this binding enhances D1-mediated Ca2+ release, is not true, according to recent experiments in Bergson's group.

"Resequencing of the cDNA clone obtained in the Y2H screen resolved a particularly GC-rich region upstream of the calcyon start codon that had been misread before and indicated that the calcyon coding sequence is out of frame with the GAL4 activation domain. In view of this, we conducted other in vitro studies and found that calcyon and D1Rs do not directly interact. Further, we also determined that although D1Rs do stimulate intracellular Ca2+ release after priming of cells or neurons with Gq-linked receptor agonists, calcyon does not significantly enhance this response," the researchers write.

What might be the impact of this retraction? The original paper has been cited by 103 other papers, according to Google Scholar. In particular, calcyon has been targeted by researchers doing postmortem research in schizophrenia, and several groups have reported alterations in calcyon in schizophrenia brain (Baracskay et al., 2006; Clinton et al., 2005; Luo et al., 2004; Koh et al., 2003). Assuming these findings reflect real perturbations in schizophrenia, are they still related to dopamine neurotransmission? Perhaps there are clues in the Bergson group's recent report that calcyon participates in clathrin-mediated endocytosis (Xiao et al., 2006), which suggest a role in receptor trafficking.

A less weighty matter is the fact that the name "calcyon" was chosen as shorthand for "calcium on." Will the protein need a new moniker? We invite your input on whether subsequent data need to be reinterpreted in light of this new information.—Hakon Heimer.

Reference:
Lezcano N, Bergson C, Mrzljak L, Levenson R. Retraction. Science. 2006 Dec 15;314(5806):1681. Abstract

Q&A with Clare Bergson

Q: Where does this leave calcyon, especially vis-à-vis schizophrenia?
A: Based on our findings that calcyon participates in clathrin-mediated endocytosis, calcyon potentially regulates the function of a wide variety of neurotransmitter receptors, both G-protein linked as well as ligand gated ion channel-type receptors, since receptor desensitization in many cases involves clathrin-mediated endocytosis. Consistent with this, we reported at the recent Annual Meeting of the Society for Neuroscience in Atlanta that calcyon plays an important role in some paradigms of synaptic plasticity due to postsynaptic effects on AMPA receptor internalization (Trantham-Davidson et al., 2006).

Notably, activity-regulated AMPA receptor internalization and long-term synaptic depression (LTD), both of which depend on clathrin-mediated endocytosis, are greatly impaired in CA1 neurons from calcyon knockout mice. Calcyon levels are increased in the postmortem tissue from schizophrenic brains (Koh et al., 2003; Bai et al., 2004; Clinton et al., 2005; Baracskay et al., 2006). The requirement for calcyon for LTD suggests a number of potential connections with the symptoms and pathology of schizophrenia, as synaptic weakening due to reduced levels of surface AMPA receptor correlates with decreased spine size (Schikorski and Stevens, 1997; Matsuzaki et al., 2001). Further, decreased spine density of pyramidal cells in dorsolateral prefrontal cortex (Garey et al., 1998; Lewis and Levitt, 2002; Glantz and Lewis, 2000) and hippocampus (Law et al., 2004) is among the anatomical abnormalities found in schizophrenic brain. Of late, it has been frequently speculated that disruptions in synaptic plasticity might play a role in neurodevelopmental disorders, such as schizophrenia (Stephan et al., 2006; Harrison and Weinberger, 2005; Gisabella et al., 2005). However, mechanistic evidence supporting such a connection is limited. Future studies should lead to a better understanding of the role of calcyon in synaptic weakening so that it will be possible to directly test how upregulation of calcyon might lead to disruption of circuits and “dysconnectivity” observed in schizophrenia.

Chlorpromazine represents another intriguing link. This typical antipsychotic was one of the first drugs used successfully in the treatment of schizophrenia. In addition to its action at DA, serotonin, and cholinergic receptors, chlorpromazine also interferes with clathrin-mediated endocytosis (Wang et al., 1993).

Comments on News and Primary Papers
Comment by:  John McGrath, SRF Advisor
Submitted 7 January 2007
Posted 7 January 2007

Charles Darwin noted “To kill an error is as good a service as, and sometimes even better than, the establishing of a new truth or fact.” It is a healthy sign that scientists can acknowledge mistakes, and a credit to the journals and editors who publish corrections. I congratulate Lezcano and colleagues for this retraction, and thank Clare Bergson for the helpful update.

View all comments by John McGrath