Dark continuous noise from visual pigment as a major mechanism underlying rod-cone difference in light sensitivity.

Retinal rods and cones underlie scotopic and photopic vision, respectively. Their pigments exhibit spontaneous isomerizations (quantal noise) in darkness due to intrinsic thermal energy. This quantal noise, albeit exceedingly low in rods, dictates the light threshold for scotopic vision.

Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y.

An ACC-VTA-ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences.

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACC) projecting to the VTA indirectly inhibit dopaminergic neurons (VTA) by activating local GABAergic interneurons (VTA), and this effect is reinforced after nerve injury.

Ca -independent transmission at the central synapse formed between dorsal root ganglion and dorsal horn neurons.

A central principle of synaptic transmission is that action potential-induced presynaptic neurotransmitter release occurs exclusively via Ca -dependent secretion (CDS). The discovery and mechanistic investigations of Ca -independent but voltage-dependent secretion (CiVDS) have demonstrated that the action potential per se is sufficient to trigger neurotransmission in the somata of primary sensory and sympathetic neurons in mammals. One key question remains, however, whether CiVDS contributes to central synaptic transmission.

Synaptotagmin-1 is a bidirectional Ca sensor for neuronal endocytosis.

Exocytosis and endocytosis are tightly coupled. In addition to initiating exocytosis, Ca2+ plays critical roles in exocytosis–endocytosis coupling in neurons and nonneuronal cells. Both positive and negative roles of Ca2+ in endocytosis have been reported; however, Ca2+ inhibition in endocytosis remains debatable with unknown mechanisms.

Light-dependent photoreceptor orientation in mouse retina.

Almost a century ago, Stiles and Crawford reported that the human eye is more sensitive to light entering through the pupil center than through its periphery (Stiles-Crawford effect). This psychophysical phenomenon, later found to correlate with photoreceptor orientation toward the pupil, was dynamically phototropic, adjustable within days to an eccentrically displaced pupil. For decades, this phototropism has been speculated to involve coordinated movements of the rectilinear photoreceptor outer and inner segments.

Dark noise and retinal degeneration from D190N-rhodopsin.

Numerous rhodopsin mutations have been implicated in night blindness and retinal degeneration, often with unclear etiology. D190N-rhodopsin (D190N-Rho) is a well-known inherited human mutation causing retinitis pigmentosa. Both higher-than-normal spontaneous-isomerization activity and misfolding/mistargeting of the mutant protein have been proposed as causes of the disease, but neither explanation has been thoroughly examined.

Ca-independent but voltage-dependent quantal catecholamine secretion (CiVDS) in the mammalian sympathetic nervous system.

Action potential-induced vesicular exocytosis is considered exclusively Ca dependent in Katz's Ca hypothesis on synaptic transmission. This long-standing concept gets an exception following the discovery of Ca-independent but voltage-dependent secretion (CiVDS) and its molecular mechanisms in dorsal root ganglion sensory neurons. However, whether CiVDS presents only in sensory cells remains elusive.

Impaired D2 receptor-dependent dopaminergic transmission in prefrontal cortex of awake mouse model of Parkinson's disease.

The loss-of-function mutation in PARK7/DJ-1 is one of the most common causes of autosomal recessive Parkinson's disease, and patients carrying PARK7 mutations often exhibit both a progressive movement disorder and emotional impairment, such as anxiety. However, the causes of the emotional symptom accompanying PARK7-associated and other forms of Parkinson's disease remain largely unexplored. Using two-photon microscopic Ca2+ imaging in awake PARK7-/- and PARK7+/+ mice, we found that (i) PARK7-/- neurons in the frontal association cortex showed substantially higher circuit activity recorded as spontaneous somatic Ca2+ signals; (ii) both basal and evoked dopamine release remained intact, as determined by both electrochemical dopamine recordings and high performance liquid chromatography in vivo; (iii) D2 receptor expression was significantly decreased in postsynaptic frontal association cortical neurons, and the hyper-neuronal activity were rescued by D2 receptor intervention using either local pharmacology or viral D2 receptor over-expression; and (iv) PARK7-/- mice showed anxiety-like behaviours that were rescued by either local D2 receptor pharmacology or overexpression.

Differential Co-release of Two Neurotransmitters from a Vesicle Fusion Pore in Mammalian Adrenal Chromaffin Cells.

Co-release of multiple neurotransmitters from secretory vesicles is common in neurons and neuroendocrine cells. However, whether and how the transmitters co-released from a single vesicle are differentially regulated remains unknown. In matrix-containing dense-core vesicles (DCVs) in chromaffin cells, there are two modes of catecholamine (CA) release from a single DCV: quantal and sub-quantal.

Synaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson's disease-like pathology.

Loss-of-function mutations in Parkin are the most common causes of autosomal recessive Parkinson's disease (PD). Many putative substrates of parkin have been reported; their pathogenic roles, however, remain obscure due to poor characterization, particularly in vivo. Here, we show that synaptotagmin-11, encoded by a PD-risk gene SYT11, is a physiological substrate of parkin and plays critical roles in mediating parkin-linked neurotoxicity.

Ca2.2 Gates Calcium-Independent but Voltage-Dependent Secretion in Mammalian Sensory Neurons.

Action potential induces membrane depolarization and triggers intracellular free Ca concentration (Ca)-dependent secretion (CDS) via Ca influx through voltage-gated Ca channels. We report a new type of somatic exocytosis triggered by the action potential per se-Ca-independent but voltage-dependent secretion (CiVDS)-in dorsal root ganglion neurons. Here we uncovered the molecular mechanism of CiVDS, comprising a voltage sensor, fusion machinery, and their linker.

Ligand- and voltage-gated Ca channels differentially regulate the mode of vesicular neuropeptide release in mammalian sensory neurons.

Neuropeptides released from dorsal root ganglion (DRG) neurons play essential roles in the neurotransmission of sensory inputs, including those underlying nociception and pathological pain. Neuropeptides are released from intracellular vesicles through two modes: a partial release mode called "kiss-and-run" (KAR) and a full release mode called "full fusion-like" (FFL). Using total internal reflection fluorescence (TIRF) microscopy, we traced the release of pH-sensitive green fluorescent protein-tagged neuropeptide Y (pHluorin-NPY) from individual dense-core vesicles in the soma and axon of single DRG neurons after Ca influx through either voltage-gated Ca channels (VGCCs) or ligand-gated transient receptor potential vanilloid 1 (TRPV1) channels.

Molecular Mechanisms for the Coupling of Endocytosis to Exocytosis in Neurons.

Neuronal communication and brain function mainly depend on the fundamental biological events of neurotransmission, including the exocytosis of presynaptic vesicles (SVs) for neurotransmitter release and the subsequent endocytosis for SV retrieval. Neurotransmitters are released through the Ca- and SNARE-dependent fusion of SVs with the presynaptic plasma membrane. Following exocytosis, endocytosis occurs immediately to retrieve SV membrane and fusion machinery for local recycling and thus maintain the homeostasis of synaptic structure and sustained neurotransmission.

Intracellular TRPA1 mediates Ca2+ release from lysosomes in dorsal root ganglion neurons.

Transient receptor potential A1 (TRPA1) is a nonselective cation channel implicated in thermosensation and inflammatory pain. In this study, we show that TRPA1 (activated by allyl isothiocyanate, acrolein, and 4-hydroxynonenal) elevates the intracellular Ca concentration ([Ca]) in dorsal root ganglion (DRG) neurons in the presence and absence of extracellular Ca Pharmacological and immunocytochemical analyses revealed the presence of TRPA1 channels both on the plasma membrane and in endolysosomes. Confocal line-scan imaging demonstrated Ca signals elicited from individual endolysosomes ("lysosome Ca sparks") by TRPA1 activation.

Synaptotagmin-11 inhibits clathrin-mediated and bulk endocytosis.

Precise and efficient endocytosis is essential for vesicle recycling during a sustained neurotransmission. The regulation of endocytosis has been extensively studied, but inhibitors have rarely been found. Here, we show that synaptotagmin-11 (Syt11), a non-Ca(2+)-binding Syt implicated in schizophrenia and Parkinson's disease, inhibits clathrin-mediated endocytosis (CME) and bulk endocytosis in dorsal root ganglion neurons.

Gain-of-function mutations in SCN11A cause familial episodic pain.

Many ion channel genes have been associated with human genetic pain disorders. Here we report two large Chinese families with autosomal-dominant episodic pain. We performed a genome-wide linkage scan with microsatellite markers after excluding mutations in three known genes (SCN9A, SCN10A, and TRPA1) that cause similar pain syndrome to our findings, and we mapped the genetic locus to a 7.