Functional characterization of ether-à-go-go-related gene potassium channels in midbrain dopamine neurons - implications for a role in depolarization block.

Bursting activity by midbrain dopamine neurons reflects the complex interplay between their intrinsic pacemaker activity and synaptic inputs. Although the precise mechanism responsible for the generation and modulation of bursting in vivo has yet to be established, several ion channels have been implicated in the process. Previous studies with nonselective blockers suggested that ether-à-go-go-related gene (ERG) K(+) channels are functionally significant.

Tmem16A encodes the Ca2+-activated Cl- channel in mouse submandibular salivary gland acinar cells.

Activation of an apical Ca(2+)-dependent Cl(-) channel (CaCC) is the rate-limiting step for fluid secretion in many exocrine tissues. Here, we compared the properties of native CaCC in mouse submandibular salivary gland acinar cells to the Ca(2+)-gated Cl(-) currents generated by Tmem16A and Best2, members from two distinct families of Ca(2+)-activated Cl(-) channels found in salivary glands. Heterologous expression of Tmem16A and Best2 transcripts in HEK293 cells produced Ca(2+)-activated Cl(-) currents with time and voltage dependence and inhibitor sensitivity that resembled the Ca(2+)-activated Cl(-) current found in native salivary acinar cells.

Activity-dependent vesicular monoamine transporter-mediated depletion of the nucleus supports somatic release by serotonin neurons.

Packaging by the vesicular monoamine transporter (VMAT) is essential for mood-controlling serotonin transmission but has not been assayed during activity. Here, two-photon imaging of the fluorescent serotonin analog 5,7-dihydroxytryptamine and three-photon imaging of endogenous serotonin were used to study vesicular packaging as it supports release from the soma of serotonin neurons. Glutamate receptor activation in dorsal raphe brain slice evoked somatic release that was mediated solely by vesicle exocytosis.

Cav1.3 channel voltage dependence, not Ca2+ selectivity, drives pacemaker activity and amplifies bursts in nigral dopamine neurons.

Ca(v)1.3 (alpha 1D) L-type Ca(2+) channels have been implicated in substantia nigra (SN) dopamine (DA) neuron pacemaking and vulnerability to Parkinson's disease. These effects may arise from the depolarizing current and cytoplasmic Ca(2+) elevation produced by Ca(v)1.

Dopamine neuron responses depend exponentially on pacemaker interval.

Midbrain dopamine neuron activity results from the integration of the responses to metabo- and ionotropic receptors with the postsynaptic excitability of these intrinsic pacemakers. Interestingly, intrinsic pacemaker rate varies greatly between individual dopamine neurons and is subject to short- and long-term regulation. Here responses of substantia nigra dopamine neurons to defined dynamic-clamp stimuli were measured to quantify the impact of cell-to-cell variation in intrinsic pacemaker rate.

Looking chloride channels straight in the eye: bestrophins, lipofuscinosis, and retinal degeneration.

Recent evidence suggests that Cl(-) ion channels are important for retinal integrity. Bestrophin Cl(-) channel mutations in humans are genetically linked to a juvenile form of macular degeneration, and disruption of some ClC Cl(-) channels in mice leads to retinal degeneration. In both cases, accumulation of lipofuscin pigment is a key feature of the cellular degeneration.

Calcium-activated chloride channels.

Calcium-activated chloride channels (CaCCs) play important roles in cellular physiology, including epithelial secretion of electrolytes and water, sensory transduction, regulation of neuronal and cardiac excitability, and regulation of vascular tone. This review discusses the physiological roles of these channels, their mechanisms of regulation and activation, and the mechanisms of anion selectivity and conduction. Despite the fact that CaCCs are so broadly expressed in cells and play such important functions, understanding these channels has been limited by the absence of specific blockers and the fact that the molecular identities of CaCCs remains in question.

Chloride accumulation in mammalian olfactory sensory neurons.

The generation of an excitatory receptor current in mammalian olfactory sensory neurons (OSNs) involves the sequential activation of two distinct types of ion channels: cAMP-gated Ca(2+)-permeable cation channels and Ca(2+)-gated Cl(-) channels, which conduct a depolarizing Cl(-) efflux. This unusual transduction mechanism requires an outward-directed driving force for Cl(-), established by active accumulation of Cl(-) within the lumen of the sensory cilia. We used two-photon fluorescence lifetime imaging microscopy of the Cl(-)-sensitive dye 6-methoxy-quinolyl acetoethyl ester to measure the intracellular Cl(-) concentration in dendritic knobs of OSNs from mice and rats.