Drew Linsley

Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3

Significance Skeletal muscle contractions are regulated by a process called excitation–contraction (EC) coupling, and defects in it are associated with numerous human myopathies. Recently, stac3 (SH3 and cysteine-rich domain 3) was identified as a key regulator of EC coupling and a STAC3 mutation as causal for the debilitating Native American myopathy (NAM). We now show that Stac3 controls EC coupling by regulating Ca2+ channels in muscles. Both the NAM mutation and a mutation that leads to the loss of Stac3 decrease the amount, organization, stability, and voltage sensitivity of Ca2+ channels. Furthermore, we find evidence that the NAM allele of STAC3 is linked to malignant hyperthermia, a common pharmacogenic disorder. These findings define critical roles for Stac3 in muscle contraction and human disease. Skeletal muscle contractions are initiated by an increase in Ca2+ released during excitation–contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca2+ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native American myopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3NAM myofibers exhibited increased caffeine-induced Ca2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+ in internal stores, which is consistent with increased SR luminal Ca2+. These findings define critical roles for Stac3 in EC coupling and human disease.

Complementary surrounds explain diverse contextual phenomena across visual modalities.

Context is known to affect how a stimulus is perceived. A variety of illusions have been attributed to contextual processing—from orientation tilt effects to chromatic induction phenomena, but their neural underpinnings remain poorly understood. Here, we present a recurrent network model of classical and extraclassical receptive fields that is constrained by the anatomy and physiology of the visual cortex. A key feature of the model is the postulated existence of near- versus far- extraclassical regions with complementary facilitatory and suppressive contributions to the classical receptive field. The model accounts for a variety of contextual illusions, reveals commonalities between seemingly disparate phenomena, and helps organize them into a novel taxonomy. It explains how center-surround interactions may shift from attraction to repulsion in tilt effects, and from contrast to assimilation in induction phenomena. The model further explains enhanced perceptual shifts generated by a class of patterned background stimuli that activate the two opponent extraclassical regions cooperatively. Overall, the ability of the model to account for the variety and complexity of contextual illusions provides computational evidence for a novel canonical circuit that is shared across visual modalities.