Association Study of , , , and Single-Nucleotide Polymorphisms with Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is a complex chronic disease characterized by decreased insulin secretion and the development of insulin resistance. Previous genome-wide association studies demonstrated that single-nucleotide polymorphisms (SNPs) present in genes coding for ion channels involved in insulin secretion increase the risk of developing this disease. We determined the association of 16 SNPs found in , , , and genes and the increased probability of developing T2DM.

The Influence of Sex Steroid Hormone Fluctuations on Capsaicin-Induced Pain and TRPV1 Expression.

Sexual dimorphism among mammals includes variations in the pain threshold. These differences are influenced by hormonal fluctuations in females during the estrous and menstrual cycles of rodents and humans, respectively. These physiological conditions display various phases, including proestrus and diestrus in rodents and follicular and luteal phases in humans, distinctly characterized by varying estrogen levels.

Streptozotocin-Induced Diabetic Rats Showed a Differential Glycine Receptor Expression in the Spinal Cord: A GlyR Role in Diabetic Neuropathy.

In the spinal cord, attenuation of the inhibitory action of glycine is related to an increase in both inflammatory and diabetic neuropathic pain; however, the glycine receptor involvement in diabetic neuropathy has not been reported. We determined the expression of the glycine receptor subunits (α1-α3 and β) in streptozotocin-induced diabetic Long-Evans rats by qPCR and Western blot. The total mRNA and protein expression (whole spinal cord homogenate) of the α1, α3, and β subunits did not change during diabetes; however, the α2 subunit mRNA, but not the protein, was overexpressed 45 days after diabetes induction.

Regulation of ThermoTRP Channels by PIP2 and Cholesterol.

Transient receptor potential (TRP) ion channels are proteins that are expressed by diverse tissues and that play pivotal functions in physiology. These channels are polymodal and are activated by several stimuli. Among TRPs, some members of this family of channels respond to changes in ambient temperature and are known as thermoTRPs.

Identification of Dp140 and α1-syntrophin as novel molecular interactors of the neuronal Ca2.1 channel.

The primary function of dystrophin is to form a link between the cytoskeleton and the extracellular matrix. In addition to this crucial structural function, dystrophin also plays an essential role in clustering and organizing several signaling proteins, including ion channels. Proteomic analysis of the whole rodent brain has stressed the role of some components of the dystrophin-associated glycoprotein complex (DGC) as potential interacting proteins of the voltage-gated Ca channels of the Ca2 subfamily.

TRP channels: a journey towards a molecular understanding of pain.

The perception of nociceptive signals, which are translated into pain, plays a fundamental role in the survival of organisms. Because pain is linked to a negative sensation, animals learn to avoid noxious signals. These signals are detected by receptors, which include some members of the transient receptor potential (TRP) family of ion channels that act as transducers of exogenous and endogenous noxious cues.

TRPV1 Channel: A Noxious Signal Transducer That Affects Mitochondrial Function.

The Transient Receptor Vanilloid 1 (TRPV1) or capsaicin receptor is a nonselective cation channel, which is abundantly expressed in nociceptors. This channel is an important transducer of several noxious stimuli, having a pivotal role in pain development. Several TRPV1 studies have focused on understanding its structure and function, as well as on the identification of compounds that regulate its activity.

TRPV4: A Physio and Pathophysiologically Significant Ion Channel.

Transient Receptor Potential (TRP) channels are a family of ion channels whose members are distributed among all kinds of animals, from invertebrates to vertebrates. The importance of these molecules is exemplified by the variety of physiological roles they play. Perhaps, the most extensively studied member of this family is the TRPV1 ion channel; nonetheless, the activity of TRPV4 has been associated to several physio and pathophysiological processes, and its dysfunction can lead to severe consequences.

Steroids and TRP Channels: A Close Relationship.

Transient receptor potential (TRP) channels are remarkable transmembrane protein complexes that are essential for the physiology of the tissues in which they are expressed. They function as non-selective cation channels allowing for the signal transduction of several chemical, physical and thermal stimuli and modifying cell function. These channels play pivotal roles in the nervous and reproductive systems, kidney, pancreas, lung, bone, intestine, among others.

TRPV1: Structure, Endogenous Agonists, and Mechanisms.

The Transient Receptor Potential Vanilloid 1 (TRPV1) channel is a polymodal protein with functions widely linked to the generation of pain. Several agonists of exogenous and endogenous nature have been described for this ion channel. Nonetheless, detailed mechanisms and description of binding sites have been resolved only for a few endogenous agonists.

Parkin is transcriptionally regulated by the aryl hydrocarbon receptor: Impact on α-synuclein protein levels.

Parkin (PRKN) is a ubiquitin E3 ligase that catalyzes the ubiquitination of several proteins. Mutations in the human Parkin gene, PRKN, leads to degeneration of dopaminergic (DA) neurons, resulting in autosomal recessive early-onset parkinsonism and the loss of PRKN function is linked to sporadic Parkinson's disease (PD). Additionally, several in vitro studies have shown that overexpression of exogenous PRKN protects against the neurotoxic effects induced by a wide range of cellular stressors, emphasizing the need to study the mechanism(s) governing PRKN expression and induction.

Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity.

The study of Hutchinson-Gilford progeria syndrome (HGPS) has provided important clues to decipher mechanisms underlying aging. Progerin, a mutant lamin A, disrupts nuclear envelope structure/function, with further impairment of multiple processes that culminate in senescence. Here, we demonstrate that the nuclear protein export pathway is exacerbated in HGPS, due to progerin-driven overexpression of CRM1, thereby disturbing nucleocytoplasmic partitioning of CRM1-target proteins.

Cholesterol as a Key Molecule That Regulates TRPV1 Channel Function.

Cholesterol is the one of the major constituents of cell membranes providing these structures with a certain degree of rigidity. Proteins, such as ion channels, are molecules inserted in cell membranes and their activity is regulated by cholesterol and other molecules of a lipidic nature present in them. The molecular mechanisms underlying the regulation of ion channels by lipids and similar molecules have been an object of study for several years.

Molecular Interplay Between the Sigma-1 Receptor, Steroids, and Ion Channels.

Cell excitability is tightly regulated by the activity of ion channels that allow for the passage of ions across cell membranes. Ion channel activity is controlled by different mechanisms that change their gating properties, expression or abundance in the cell membrane. The latter can be achieved by forming complexes with a diversity of proteins like chaperones such as the Sigma-1 receptor (Sig-1R), which is one with unique features and exhibits a role as a ligand-operated chaperone.

The intracellular domain of β-dystroglycan mediates the nucleolar stress response by suppressing UBF transcriptional activity.

β-dystroglycan (β-DG) is a key component of multiprotein complexes in the plasma membrane and nuclear envelope. In addition, β-DG undergoes two successive proteolytic cleavages that result in the liberation of its intracellular domain (ICD) into the cytosol and nucleus. However, stimuli-inducing ICD cleavage and the physiological relevance of this proteolytic fragment are largely unknown.

Lysophosphatidic Acid and Ion Channels as Molecular Mediators of Pain.

Lysophosphatidic acid or LPA is a phospholipid which has been extensively linked to the generation and maintenance of pain. Several ion channels have also been shown to participate in this pathological process but the link between LPA and these proteins in pain has just recently gained interest. In this respect, the field has advanced by determining the molecular mechanisms by which LPA promotes changes in the function of some ion channels.

Different agonists induce distinct single-channel conductance states in TRPV1 channels.

The TRPV1 ion channel is a membrane protein that is expressed in primary afferent nociceptors, where it is activated by a diverse array of stimuli. Our prior work has shown that this channel is activated by lysophosphatidic acid (LPA), an unsaturated lysophospholipid that is produced endogenously and released under certain pathophysiological conditions, resulting in the sensation of pain. Macroscopic currents activated by saturating concentrations of LPA applied to excised membrane patches are larger in magnitude than those activated by saturating concentrations of capsaicin, which causes near-maximal TRPV1 open probability.

TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain.

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain.

Multiple Mechanisms of Regulation of Transient Receptor Potential Ion Channels by Cholesterol.

The transient receptor potential (TRP) family of ion channels is constituted by several nonselective cation channels that are activated by diverse stimuli and that function as polymodal receptors. TRP ion channels are expressed in neural and nonneural tissues where they play important roles in cell physiology. The activation of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by some natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity.

Regulation of thermoTRPs by lipids.

The family of Transient Receptor Potential (TRP) ion channels is constituted by 7 subfamilies among which are those that respond to temperature, the thermoTRPs. These channels are versatile molecules of a polymodal nature that have been shown to be modulated in various fashions by molecules of a lipidic nature. Some of these molecules interact directly with the channels on specific regions of their structures and some of these promote changes in membrane fluidity or modify their gating properties in response to their agonists.

Inhibition of TRPV1 channels by a naturally occurring omega-9 fatty acid reduces pain and itch.

The transient receptor potential vanilloid 1 (TRPV1) ion channel is mainly found in primary nociceptive afferents whose activity has been linked to pathophysiological conditions including pain, itch and inflammation. Consequently, it is important to identify naturally occurring antagonists of this channel. Here we show that a naturally occurring monounsaturated fatty acid, oleic acid, inhibits TRPV1 activity, and also pain and itch responses in mice by interacting with the vanilloid (capsaicin)-binding pocket and promoting the stabilization of a closed state conformation.

Organic toxins as tools to understand ion channel mechanisms and structure.

Ion channels constitute a varied class of membrane proteins with pivotal roles in cellular physiology and that are fundamental for neuronal signaling, hormone secretion and muscle contractility. Hence, it is not unanticipated that toxins from diverse organisms have evolved to modulate the activity of ion channels. For instance, animals such as cone snails, scorpions, spiders and snakes use toxins to immobilize and capture their prey by affecting ion channel function.