oa Editorial [ Hot Topic: Sigma Receptor Research: Progress Towards Diagnostic and Therapeutic Uses of Sigma Ligands (Executive Guest Editor: Carmen Abate )]

Sigma (σ ) receptor history started in 1976 when Martin et al. proposed the σ opioid receptors (“ σ-opioid”) to account for the psychotomimetic effects that the benzomorphan SKF-10,047 (N-allylnormetazocine) caused in the chronic spinal dog model and which were blocked by the opioid antagonist naloxone [1]. Later Su et al. identified a binding site which was labeled by [3H]-SKF-10,047 [2] but which was insensitive to naloxone and naltrexone. This finding led to the hypothesis that the protein identified by Su and co-workers was not the - opioid receptor proposed by Martin, so that the name of the binding site was changed to the ‘ receptor’ to distinguish it from the opioid receptor. Evidence that SKF-10,047 and other benzomorphans displayed high affinity for the phencyclidine (PCP) site at the NMDA receptor, and conversely that PCP displayed affinity for the receptor, led to confusion so that sites named PCP/ were introduced for a while. However, subsequent ligand binding studies dispelled this confusion and receptors were finally considered as non-opioid, non-PCP brain receptors. The availability of more ligands led in the early 1990s to the identification of two subtypes of receptors, namely 1 and 2, and soon thereafter the 1 subtype was cloned from guinea pig liver first and from mouse and human cells later [3,4]. The 1 receptors displayed high homology among species but no homology with other known mammalian proteins. Several structures have been proposed for 1 receptors and the most accepted model today shows that the 1 subtype is made of three hydrophobic regions, two of which are transmebrane-spanning segments with the NH2 and COOH termini on the same side of the cell compartment. The binding sites within this subtype have also been identified and several pharmacophoric models have been built for the 1 subtype with the early model proposed by Glennon and co-workers being among the most inspiring [5]. In recent studies two endogenous 1 ligands have been proposed: D-erythro-sphingosine [6] and N,Ndimethyltryptamine (DMT) with the latter being controversial [7,8]. Thorough efforts have been directed towards the elucidation of the signaling mechanism but more studies are still needed to clarify the roles and pathways activated by this subtype. The association of the 1 subtype with G-protein coupled receptors has been finally ruled out, whereas it has been extensively shown that 1 is involved in the regulation of Ca2+ level via IP3 receptors on the endoplasmic reticulum (ER) where a chaperone function for the cross-talk between the ER and mithocondria has been suggested [9]. In addition, 1 receptor modulation of distinct K+ channels and NMDA receptor-coupled ion channels have been demonstrated. All the above actions, together with the involvement in cell lipid compartmentalization suggested for this subtype, give good reason for a role of 1 proteins in cell proliferation. 1 Receptors have been shown to modulate a number of central neurotransmitter systems, and this evidence together with the early findings that several antipsychotic drugs bind with high affinity to 1 subtypes have linked these proteins to important brain functions since their proposal. Increasing evidence implicates this subtype in pathologies such as anxiety, depression, schizophrenia, drug addiction, Alzheimer's disease and movement disorders (such as Parkinson's disease and juvenile amyotrophic sclerosis which has been recently shown to be caused by a mutation to the 1 gene [10]). Noteworthy roles in neuroprotection and neuroplasticity have been suggested for this subtype: 1 ligands protect against brain ischemia and potentiate neurite outgrowth [11,12]. Pharmacological studies and behavioural models for certain CNS diseases have shed light to promising ligands some of which have entered clinical trials. The availability of 1 knockout mice, which are viable and fertile, but which show a difference from the wild-type animals when challenged in behavioural experiments, will likely help to better understand 1 involvement in the CNS [13]. Although initial research was focused on receptors within the CNS, it has been shown that both subtypes are present in peripheral organs at least with the same density as in the CNS, and they are over-expressed in a variety of peripheral and brain human tumors. This evidence has prompted researchers to develop radioligands for the diagnosis of tumors for PET and SPECT analyses with encouraging results which have been recently reviewed in detail [14,15]....