Kv2 channels contribute to neuronal activity within the vagal afferent-nTS reflex arc.

Diversity in the functional expression of ion channels contributes to the unique patterns of activity generated in visceral sensory A-type myelinated neurons versus C-type unmyelinated neurons in response to their natural stimuli. In the present study, Kv2 channels were identified as underlying a previously uncharacterized delayed rectifying potassium current expressed in both A- and C-type nodose ganglion neurons. Kv2.

Voltage-gated potassium channel proteins and stereoselective S-nitroso-l-cysteine signaling.

S-nitroso-l-cysteine (L-CSNO) behaves as a ligand. Its soluble guanylate cyclase-independent (sGC-independent) effects are stereoselective - that is, not recapitulated by S-nitroso-d-cysteine (D-CSNO) - and are inhibited by chemical congeners. However, candidate L-CSNO receptors have not been identified.

Simultaneous cardiac and respiratory inhibition during seizure precedes death in the DBA/1 audiogenic mouse model of SUDEP.

This study was designed to evaluate cardiac and respiratory dysfunction in a mouse model of sudden unexpected death in epilepsy i.e., SUDEP.

TRPV1 channels contribute to spontaneous glutamate release in nucleus tractus solitarii following chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) reduces afferent-evoked excitatory postsynaptic currents (EPSCs) but enhances basal spontaneous (s) and asynchronous (a) EPSCs in second-order neurons of nucleus tractus solitarii (nTS), a major area for cardiorespiratory control. The net result is an increase in synaptic transmission. The mechanisms by which this occurs are unknown.

ApoL1 Overexpression Drives Variant-Independent Cytotoxicity.

Coding variants in the gene are associated with kidney diseases in African ancestral populations; yet, the underlying biologic mechanisms remain uncertain. Variant-dependent autophagic and cytotoxic cell death have been proposed as pathogenic pathways mediating kidney injury. To examine this possibility, we conditionally expressed APOL1-G0 (reference), -G1, and -G2 (variants) using a tetracycline-regulated system in HEK293 cells.

The Kv1.1 null mouse, a model of sudden unexpected death in epilepsy (SUDEP).

Objective: Kv1.1 potassium channel null mouse (NULL) exhibits spontaneous seizure-related bradycardia, dies following seizure, and has been proposed as a model for vagus-mediated SUDEP. We characterized the cardiac events surrounding sudden unexpected death in epilepsy (SUDEP) in NULL during terminal asystole for comparison to patients with epilepsy who exhibit bradycardia and terminal or nonterminal asystole during/following seizure and explored the contribution of vagal-mediated bradycardia to SUDEP.

An afferent explanation for sexual dimorphism in the aortic baroreflex of rat.

Sex differences in baroreflex (BRx) function are well documented. Hormones likely contribute to this dimorphism, but many functional aspects remain unresolved. Our lab has been investigating a subset of vagal sensory neurons that constitute nearly 50% of the total population of myelinated aortic baroreceptors (BR) in female rats but less than 2% in male rats.

Differential distribution of voltage-gated channels in myelinated and unmyelinated baroreceptor afferents.

Voltage gated ion channels (VGC) make possible the frequency coding of arterial pressure and the neurotransmission of this information along myelinated and unmyelinated fiber pathways. Although many of the same VGC isoforms are expressed in both fiber types, it is the relative expression of each that defines the unique discharge properties of myelinated A-type and unmyelinated C-type baroreceptors. For example, the fast inward Na⁺ current is a major determinant of the action potential threshold and the regenerative transmembrane current needed to sustain repetitive discharge.

The juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity.

Despite considerable effort, the identification of genes that regulate complex multigenic traits such as obesity has proven difficult with conventional methodologies. The use of a chromosome substitution strain-based mapping strategy based on deep congenic analysis overcame many of the difficulties associated with gene discovery and led to the finding that the juxtaparanodal proteins CNTNAP2 and TAG1 regulate diet-induced obesity. The effects of a mild Cntnap2 mutation on body weight were highly dependent on genetic background, as both obesity-promoting and obesity-resistant effects of Cntnap2 were observed on different genetic backgrounds.

Expression of the P/Q (Cav2.1) calcium channel in nodose sensory neurons and arterial baroreceptors.

The predominant calcium current in nodose sensory neurons, including the subpopulation of baroreceptor neurons, is the N-type channel, Cav2.2. It is also the primary calcium channel responsible for transmitter release at their presynaptic terminals in the nucleus of the solitary tract in the brainstem.

Endogenous brain-derived neurotrophic factor in the nucleus tractus solitarius tonically regulates synaptic and autonomic function.

Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, are highly expressed in the nucleus tractus solitarius (nTS), the principal target of cardiovascular primary afferent input to the brainstem. However, little is known about the role of BDNF signaling in nTS in cardiovascular homeostasis. We examined whether BDNF in nTS modulates cardiovascular function in vivo and regulates synaptic and/or neuronal activity in isolated brainstem slices.

Kv1.3 channels regulate synaptic transmission in the nucleus of solitary tract.

The voltage-gated K(+) channel Kv1.3 has been reported to regulate transmitter release in select central and peripheral neurons. In this study, we evaluated its role at the synapse between visceral sensory afferents and secondary neurons in the nucleus of the solitary tract (NTS).

KCa1.1 channel contributes to cell excitability in unmyelinated but not myelinated rat vagal afferents.

High conductance calcium-activated potassium (BK(Ca)) channels can modulate cell excitability and neurotransmitter release at synaptic and afferent terminals. BK(Ca) channels are present in primary afferents of most, if not, all internal organs and are an intriguing target for pharmacological manipulation of visceral sensation. Our laboratory has a long-standing interest in the neurophysiological differences between myelinated and unmyelinated visceral afferent function.

Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice.

Postnatal deficits in brain-derived neurotrophic factor (BDNF) are thought to contribute to pathogenesis of Rett syndrome (RTT), a progressive neurodevelopmental disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). In Mecp2-null mice, a model of RTT, BDNF deficits are most pronounced in structures important for autonomic and respiratory control, functions that are severely affected in RTT patients. However, relatively little is known about how these deficits affect neuronal function or how they may be linked to specific RTT endophenotypes.

Maitotoxin converts the plasmalemmal Ca(2+) pump into a Ca(2+)-permeable nonselective cation channel.

Maitotoxin (MTX) activates Ca(2+)-permeable nonselective cation channels and causes a dramatic increase in cytosolic free Ca(2+) concentration ([Ca(2+)](i)) in every cell examined to date, but the molecular identity of the channels involved remains unknown. A clue came from studies of a structurally related marine toxin called palytoxin (PTX). PTX binds to the plasmalemmal Na(+)-K(+)-ATPase (NKA) and converts the Na(+) pump into a nonselective cation channel.

Dopamine inhibits N-type channels in visceral afferents to reduce synaptic transmitter release under normoxic and chronic intermittent hypoxic conditions.

Glutamatergic synaptic currents elicited in second-order neurons in the nucleus of the solitary tract (nTS) by activation of chemosensory and other visceral afferent fibers are severely reduced following 10 days of chronic intermittent hypoxia (CIH). The mechanism by which this occurs is unknown. A strong candidate for producing the inhibition is dopamine, which is also released from the presynaptic terminals and which we have shown exerts a tonic presynaptic inhibition on glutamate release.

Distribution of voltage-gated potassium and hyperpolarization-activated channels in sensory afferent fibers in the rat carotid body.

The chemosensory glomus cells of the carotid body (CB) detect changes in O2 tension. Carotid sinus nerve fibers, which originate from peripheral sensory neurons located within the petrosal ganglion, innervate the CB. Release of transmitter from glomus cells activates the sensory afferent fibers to transmit information to the nucleus of the solitary tract in the brainstem.

The KCNQ/M-current modulates arterial baroreceptor function at the sensory terminal in rats.

The ion channels responsible for the pattern and frequency of discharge in arterial baroreceptor terminals are, with few exceptions, unknown. In this study we examined the contribution of KCNQ potassium channels that underlie the M-current to the function of the arterial baroreceptors. Labelled aortic baroreceptor neurons, immunohistochemistry and an isolated aortic arch preparation were used to demonstrate the presence and function of KCNQ2, KCNQ3 and KCNQ5 channels in aortic baroreceptors.

Regulation of the cellular localization and function of human transient receptor potential channel 1 by other members of the TRPC family.

Members of the Canonical Transient Receptor Potential (TRPC) family of ionic channels are able to form homo- and heterotetrameric channels. Depending on the study, TRPC1 has been detected on both the surface and inside the cell, probably in the endoplasmic reticulum (ER). Likewise, TRPC1 has been described both as a store-operated channel and as one unable to function when forming a homotetramer.

Adaptive depression in synaptic transmission in the nucleus of the solitary tract after in vivo chronic intermittent hypoxia: evidence for homeostatic plasticity.

The respiratory system is highly pliable in its adaptation to low-oxygen (hypoxic) environments. After chronic intermittent hypoxia (CIH), alterations in the regulation of cardiorespiratory system become persistent because of changes in the peripheral chemoreceptor reflex. We present evidence for the induction of a novel form of homeostatic plasticity in this reflex pathway in the nucleus tractus solitarius (NTS), the site of termination of the chemosensory afferent fibers.

KCNQ/M-currents contribute to the resting membrane potential in rat visceral sensory neurons.

The M-current is a slowly activating, non-inactivating potassium current that has been shown to be present in numerous cell types. In this study, KCNQ2, Q3 and Q5, the molecular correlates of M-current in neurons, were identified in the visceral sensory neurons of the nodose ganglia from rats through immunocytochemical studies. All neurons showed expression of each of the three proteins.

TRPC channels as signal transducers.

The study of the TRPC cation channels as signal transducers in sensory neurons is in its infancy. Mechanoreceptors that monitor arterial pressure are prime candidates for the involvement of TRPC channels as either primary mechanical transducers or as modulators of the transduction process. Their activity patterns can be regulated by growth factors such as BDNF and by a variety of ligands that activate Gq-coupled receptors, mechanisms that have been shown in heterologous expression systems to activate TRPC channels.

Kv1.1 deletion augments the afferent hypoxic chemosensory pathway and respiration.

Mutations in the potassium channel gene Kv1.1 are associated with human episodic ataxia type 1 (EA-1) syndrome characterized by movement disorders and epilepsy. Ataxic episodes in EA-1 patients are often associated with exercise or emotional stress, which suggests a prominent role for the autonomic nervous system.

Distribution of TRPC channels in a visceral sensory pathway.

Until recently most of the published studies addressing the mechanisms of activation of TRPC channels have been carried out in heterologous expression systems. Lack of specific antagonists for the TRPC channels has hampered functional studies of endogenous channels. We approached the role of TRPC channels in native tissue with a study of the distribution of the channel proteins in the carotid chemosensory pathway in the rat.