Chief among these are modulation of Ca2+ release, modulation of cardiac myocyte contractility, and inhibition of voltage gated K+ channels. The reasons for these effects are not well understood, even though σ1 receptors have been linked circumstantially to a wide variety of signal transduction pathways. Links between σ1 receptors and G-proteins have been suggested such as σ1 receptor antagonists showing GTP-sensitive high-affinity binding; there is also, however, some evidence against a G-protein coupled hypothesis. The σ1 receptor has been shown to appear in a complex with voltage gated K+ channels (Kv1.4 and Kv1.5), leading to the idea that σ1 receptors are auxiliary subunits. σ1 receptors apparently co-localize with IP3 receptors on the endoplasmic reticulum where they may be involved in preventing endoplasmic reticulum stress in neurodegenerative diseases . Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes. The wide scope and effect of ligand binding on σ1 receptors has led some to believe that σ1 receptors are intracellular signal transduction amplifiers.  σ1 receptor knockout mice were created in 2009 to study the effects of endogenous DMT. Strangely, the mice demonstrated no overt phenotype. As expected, however, they did lack locomotor response to the σ ligand (+)-SKF-10,047 and displayed reduced response to formalin induced pain. Speculation has focused on the ability of other receptors in the σ family ("e.g.", σ2, with similar binding properties) to compensate for the lack of σ1 receptor. Mutations in sigma-1 receptor have been associated with distal spinal muscular atrophy type 2. The following ligands have high affinity for the σ1 receptor and possess high binding selectivity over the subtype σ2: Agonists:  Antagonists: Positive allosteric modulators (PAMs):  Uncategorized: Agents exist that have high σ1 affinity but either lack subtype selectivity or have high affinity at other binding sites, thus being more or less [[dirty drug|dirty]]/multifunctional, like [[haloperidol]]. Furthermore, there is a wide range of agents with an at least moderate σ1 involvement in their binding profile.