The Sigma Receptor: Evolution of the Concept in Neuropsychopharmacology

Abstract

Although originally proposed as a subtype of opioid receptors, the sigma receptor is now confirmed to be a non-opioid receptor that binds diverse classes of psychotropic drugs. Sigma receptors are subdivided into two subtypes, sigma-1 and sigma-2. The sigma-1 receptor is a 25-kDa protein possessing one putative transmembrane domain and an endoplasmic reticulum retention signal. Sigma-1 receptors are highly expressed in deeper laminae of the cortex, olfactory bulb, nuclei of mesencephalon, hypothalamus, and Purkinje cells in the brain. Sigma-1 receptors are predominantly localized at the endoplasmic reticulum of both neurons and oligodendrocytes. From behavioral studies, sigma-1 receptors were shown to be involved in higher-ordered brain functions including memory and drug dependence. The actions mediated by sigma-1 receptors at the cellular level can be considered either as acute or chronic. The acute actions include the modulation of ion channels (i.e., K+ channel, NMDA receptors, IP3 receptors) and the sigma-1 receptor translocation. Chronic actions of sigma-1 receptors are basically considered to be the result of an up- or down regulation of the sigma-1 receptor itself. For example, the upregulation of sigma-1 receptors per se, even without exogenous ligands, promotes cellular differentiation and reconstitution of lipid microdomains (lipid rafts) in cultured cells. These findings together suggest that sigma-1 receptors might possess a constitutive biological activity, and that sigma-1 receptor ligands might merely work as modulators of the innate activity of this protein. Recent in vitro and in vitro studies strongly point to the possibility that sigma-1 receptors participate in membrane remodeling and cellular differentiation in the nervous system.

Direct involvement of σ-1 receptors in the dopamine D 1 receptor-mediated effects of cocaine

“…However, its biological function and even its main endogenous neurotransmitter remain enigmatic (12). Cocaine interacts with σ 1 Rs at pharmacologically relevant concentrations (12,14). In fact, reducing brain σ 1 R levels with antisense oligonucleotides attenuates the convulsive and locomotor stimulant actions of cocaine (15, 16), and σ 1 R antagonists mitigate the actions of cocaine in animal models (12,14).…”

“…The σ-1 receptor, originally proposed as a subtype of opioid receptors, is now considered to be a nonopioid receptor with two transmembrane domains, one extracellular loop and cytosolic N and C termini (12). The σ 1 R is highly expressed in the brain, including the striatum, and its association with neurons is well established (12,13).…”

“…The σ 1 R is highly expressed in the brain, including the striatum, and its association with neurons is well established (12,13). However, its biological function and even its main endogenous neurotransmitter remain enigmatic (12). Cocaine interacts with σ 1 Rs at pharmacologically relevant concentrations (12,14).…”

Cognitive impairment in depression and potential applications of antidepressants with procognitive effects

“…Они могут играть немаловажную роль при лечении де-прессии и патологической тревоги, подавлении тяги к наркотикам [54]. Изучение сигма-1-рецепторов может оказаться полезным при разработке новых анальгезирующих средств, а также средств, пода-вляющих тремор и дистонию [55,56].…”

Role of Sigma Receptor and Neurosteroids in Pain Sensation

“…6 이러한 시그마-1 수용체는 학습과 기 억 이상, 우울증, 정신분열증, 및 약물남용과 같은 중추신경 계 내의 다양한 신경 생리학적 현상에서 중요한 역할을 담당 한다. 4,7,8 시그마-1 수용체의 내인성 리간드는 아직까지 정확히 규명 되지 않은 상태이며, trace amine과 환각성 물질인 dimethyltryptamine (DMT)와 같은 체내 물질들이 내인성 리간 드로 작용할 것으로 추측된다. 9 그 중 pregnenolone 및 dehydroepiandrosterone (DHEA)을 포함한 신경스테로 이드도 시그마-1 수용체를 활성화 시키는 내인성 리간드로 작용하는 것으로 보고 되었다.…”