Journal of Physiology

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Bengt Saltin (1935-2014)

01 December 2014

Can Bayliss and Starling gut hormones cure a worldwide pandemic?

01 December 2014

Bayliss and Starling first coined the term ‘hormone’ with reference to secretin, a substance they found that was produced by the gut, but released into the blood stream to act at a distance. The intestine is now known as the largest endocrine organ in the body, and it produces numerous hormones with a wide range of functions. These include controlling appetite and energy homeostasis. Obesity is one of the greatest health threats facing the world today. At present, the only successful treatment is surgery. Bariatric procedures such as the Roux-en-Y bypass work by elevating gut hormones that induce satiety. Significant research has gone into producing versions of these hormones that can be delivered therapeutically to treat obesity. This review looks at the role of gut hormones in obesity, and the development of gut hormone-derived obesity treatments.

PKA-independent cAMP stimulation of white adipocyte exocytosis and adipokine secretion: modulations by Ca2+ and ATP

01 December 2014

We examined the effects of cAMP, Ca2+ and ATP on exocytosis and adipokine release in white adipocytes by a combination of membrane capacitance patch-clamp recordings and biochemical measurements of adipokine secretion. 3T3-L1 adipocyte exocytosis proceeded even in the complete absence of intracellular Ca2+ ([Ca2+]i; buffered with BAPTA) provided cAMP (0.1 mm) was included in the intracellular (pipette-filling) solution. Exocytosis typically plateaued within ~10 min, probably signifying depletion of a releasable vesicle pool. Inclusion of 3 mm ATP in combination with elevation of [Ca2+]i to ≥700 nm augmented the rate of cAMP-evoked exocytosis ~2-fold and exocytosis proceeded for longer periods (≥20 min) than with cAMP alone. Exocytosis was stimulated to a similar extent upon substitution of cAMP by the Epac (exchange proteins activated by cAMP) agonist 8-Br-2'-O-Me-cAMP (1 mm included in the pipette solution). Inhibition of protein kinase A (PKA) by addition of Rp-cAMPS (0.5 mm) to the cAMP-containing pipette solution was without effect. A combination of the adenylate cyclase activator forskolin (10 μm) and the phosphodiesterase inhibitor IBMX (200 μm; forsk–IBMX) augmented adiponectin secretion measured over 30 min 3-fold and 2-fold in 3T3-L1 and human subcutaneous adipocytes, respectively. This effect was unaltered by pre-loading of cells with the Ca2+ chelator BAPTA-AM and 2-fold amplified upon inclusion of the Ca2+ ionophore ionomycin (1 μm) in the extracellular solution. Adiponectin release was also stimulated by the membrane-permeable Epac agonist 8-Br-2'-O-Me-cAMP-AM but unaffected by inclusion of the membrane-permeable PKA inhibitor Rp-8-Br-cAMPS (200 μm). The adipokines leptin, resistin and apelin were present in low amounts in the incubation medium (1–6% of measured adiponectin). Adipsin was secreted in substantial quantities (50% of adiponectin concentration) but release of this adipokine was unaffected by forsk–IBMX. We propose that white adipocyte exocytosis is stimulated by cAMP/Epac-dependent but Ca2+- and PKA-independent release of vesicles residing in a readily releasable pool and that the release is augmented by a combination of Ca2+ and ATP. We further suggest that secreted vesicles chiefly contain adiponectin.

Charge at the 46th residue of connexin 50 is crucial for the gap-junctional unitary conductance and transjunctional voltage-dependent gating

01 December 2014

Gap-junction (GJ) channels are twice the length of most membrane channels, yet they often have large unitary channel conductance (j). What factors make this possibly the longest channel so efficient in passing ions are not fully clear. Here we studied the lens connexin (Cx) 50 GJs, which display one of the largest j and the most sensitive transjunctional voltage-dependent gating (Vj gating) among all GJ channels. Introduction of charged residues into a putative pore-lining domain (the first transmembrane and the first extracellular loop border) drastically altered the apparent j. Specifically, G46D and G46E increased the Cx50 j from 201 to 256 and 293 pS, respectively and the G46K channel showed an apparent j of only 20 pS. G46K also drastically altered Vj gating properties in homotypic G46K and heterotypic Cx50/G46K channels, causing an apparent loss of fast Vj-dependent gating transitions and leaving only loop gating transitions at the single channel current records. Both macroscopic and single channel currents of heterotypic Cx50/G46K channels showed a prominent rectification. Our homology structural models indicate that the pore surface electrostatic potentials are a dictating factor in determining the j. Our data demonstrate, at the whole GJ channel level, a crucial role of the surface charge properties in the first transmembrane/first extracellular border domain in determining the efficiency of ion permeation and the Vj gating of Cx50 and possibly other GJ channels.

Impact of hypocapnia and cerebral perfusion on orthostatic tolerance

01 December 2014

We examined two novel hypotheses: (1) that orthostatic tolerance (OT) would be prolonged when hyperventilatory-induced hypocapnia (and hence cerebral hypoperfusion) was prevented; and (2) that pharmacological reductions in cerebral blood flow (CBF) at baseline would lower the ‘CBF reserve’, and ultimately reduce OT. In study 1 (n = 24; aged 25 ± 4 years) participants underwent progressive lower-body negative pressure (LBNP) until pre-syncope; end-tidal carbon dioxide (P ET , CO 2) was clamped at baseline levels (isocapnic trial) or uncontrolled. In study 2 (n = 10; aged 25 ± 4 years), CBF was pharmacologically reduced by administration of indomethacin (INDO; 1.2 mg kg–1) or unaltered (placebo) followed by LBNP to pre-syncope. Beat-by-beat measurements of middle cerebral artery blood flow velocity (MCAv; transcranial Doppler), heart rate (ECG), blood pressure (BP; Finometer) and end-tidal gases were obtained continuously. In a subset of subjects’ arterial-to-jugular venous differences were obtained to examine the independent impact of hypocapnia or cerebral hypoperfusion (following INDO) on cerebral oxygen delivery and extraction. In study 1, during the isocapnic trial, P ET , CO 2 was successfully clamped at baseline levels at pre-syncope (38.3 ± 2.7 vs. 38.5 ± 2.5 mmHg respectively; P = 0.50). In the uncontrolled trial, P ET , CO 2 at pre-syncope was reduced by 10.9 ± 3.9 mmHg (P ≤ 0.001). Compared to the isocapnic trial, the decline in mean MCAv was 15 ± 4 cm s–1 (35%; P ≤ 0.001) greater in the uncontrolled trial, yet the time to pre-syncope was comparable between trials (544 ± 130 vs. 572 ± 180 s; P = 0.30). In study 2, compared to placebo, INDO reduced resting MCAv by 19 ± 4 cm s–1 (31%; P ≤ 0.001), but time to pre-syncope remained similar between trials (placebo: 1123 ± 138 s vs. INDO: 1175 ± 212 s; P = 0.53). The brain extracted more oxygen in face of hypocapnia (34% to 53%) or cerebral hypoperfusion (34% to 57%) to compensate for reductions in delivery. In summary, cerebral hypoperfusion either at rest or induced by hypocapnia at pre-syncope does not impact OT, probably due to a compensatory increase in oxygen extraction.

Interactions between beta-2 adrenoceptor gene variation, cardiovascular control and dietary sodium in healthy young adults

01 December 2014

Dietary sodium affects function of the beta-2 adrenoceptor (ADRB2). We tested the hypothesis that haplotype variation in the ADRB2 gene would influence the cardiovascular and regional vasodilator responses to sympathoexcitatory manoeuvres following low, normal and high sodium diets, and ADRB2-mediated forearm vasodilation in the high sodium condition. Seventy-one healthy young adults were grouped by double homozygous haplotypes: Arg16+Gln27 (n = 31), the rare Gly16+Gln27 (n = 10) and Gly16+Glu27 (n = 30). Using a randomized cross-over design, subjects were studied following 5 days of controlled low, normal and high sodium with 1 month or longer between diets (and low hormone phase of the menstrual cycle). All three visits utilized ECG and finger plethysmography for haemodynamic measures, and the high sodium visit included a brachial arterial catheter for forearm vasodilator responses to isoprenaline with plethysmography. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. We found a main effect of haplotype on ADRB2 density (P = 0.03) with the Gly16+Glu27 haplotype having the greatest density (low, normal, high sodium: 12.9 ± 0.9, 13.5 ± 0.9 and 13.6 ± 0.8 fmol mg–1 protein, respectively) and Arg16+Gln27 having the least (9.3 ± 0.6, 10.1 ± 0.5 and 10.3 ± 0.6  fmol mg–1 protein, respectively), but there were no sodium or haplotype effects on receptor binding conformation. In the mental stress trial, there was a main effect of haplotype on cardiac output (P = 0.04), as Arg16+Gln27 had the lowest responses. Handgrip and forearm vasodilation yielded no haplotype differences, and no correlations were present for ADRB2 density and haemodynamics. Our findings support cell-based evidence that ADRB2 haplotype influences ADRB2 protein expression independent of dietary sodium, yet the haemodynamic consequences appear modest in healthy humans.

Modulation of enteric neurons by interleukin-6 and corticotropin-releasing factor contributes to visceral hypersensitivity and altered colonic motility in a rat model of irritable bowel syndrome

01 December 2014

The search for effective therapeutic strategies for irritable bowel syndrome (IBS) is hampered by an incomplete understanding of its underlying pathophysiology. Stress and altered plasma cytokine profiles indicative of immune activation are characteristic of the disorder. The neuromodulatory effects of interleukin-6 (IL-6) and corticotropin-releasing factor receptor (CRFR) 1 in visceral pain and stress-induced defecation in the Wistar Kyoto (WKY) rat model of IBS were investigated. Sprague Dawley and WKY rats were administered anti-IL-6 receptor antibodies (xIL-6R, 0.5 mg kg–1 i.p) with or without the CRFR1 antagonist antalarmin (10 mg kg–1 i.p). Post-intervention, the pain threshold to colorectal distension and stress-induced faecal output were compared and changes in colonic mucosal protein expression were investigated. The neuro-stimulatory effects of IBS plasma on the myenteric plexus is mediated by IL-6, IL-8 and CRF. The stimulatory effects of these soluble factors on myenteric neuron excitability and colonic contractility were additive. Moreover, inhibition of IL-6 and CRF1 receptors in vivo in the WKY IBS rat model normalized stress-induced defecation (P < 0.01) and visceral pain sensitivity (P < 0.001) with associated changes in protein expression of the tight junction proteins occludin and claudin 2, the visceral pain-associated T-type calcium channel CaV3.2 and intracellular signalling molecules STAT3, SOCS3 and ERK1/2. These studies demonstrate the additive effects of immune and stress factors on myenteric neuronal excitability. Moreover, combined targeting of peripheral IL-6 and CRF1 receptors is effective in alleviating IBS-like symptoms in the WKY rat. Thus, crosstalk between stress and immune factors during IBS flares may underlie symptom exacerbation.

Cathepsin B contributes to Na+ hyperabsorption in cystic fibrosis airway epithelial cultures

01 December 2014

In cystic fibrosis (CF) lung disease, the absence of functional CF transmembrane conductance regulator results in Cl–/HCO3– hyposecretion and triggers Na+ hyperabsorption through the epithelial Na+ channel (ENaC), which contribute to reduced airway surface liquid (ASL) pH and volume. Prostasin, a membrane-anchored serine protease with trypsin-like substrate specificity has previously been shown to activate ENaC in CF airways. However, prostasin is typically inactive below pH 7.0, suggesting that it may be less relevant in acidic CF airways. Cathepsin B (CTSB) is present in both normal and CF epithelia and is secreted into ASL, but little is known about its function in the airways. We hypothesized that the acidic ASL seen in CF airways may stimulate CTSB to activate ENaC, contributing to Na+ hyperabsorption and depletion of CF ASL volume. In Xenopus laevis oocytes, CTSB triggered α- and ENaC cleavage and induced an increase in ENaC activity. In bronchial epithelia from both normal and CF donor lungs, CTSB localized to the apical membrane. In normal and CF human bronchial epithelial cultures, CTSB was detected at the apical plasma membrane and in the ASL. CTSB activity was significantly elevated in acidic ASL, which correlated with increased abundance of ENaC in the plasma membrane and a reduction in ASL volume. This acid/CTSB-dependent activation of ENaC was ameliorated with the cell impermeable, CTSB-selective inhibitor CA074, suggesting that CTSB inhibition may have therapeutic relevance. Taken together, our data suggest that CTSB is a pathophysiologically relevant protease that activates ENaC in CF airways.

Ribosome abundance regulates the recovery of skeletal muscle protein mass upon recuperation from postnatal undernutrition in mice

01 December 2014

Nutritionally-induced growth faltering in the perinatal period has been associated with reduced adult skeletal muscle mass; however, the mechanisms responsible for this are unclear. To identify the factors that determine the recuperative capacity of muscle mass, we studied offspring of FVB mouse dams fed a protein-restricted diet during gestation (GLP) or pups suckled from postnatal day 1 (PN1) to PN11 (E-UN), or PN11 to PN22 (L-UN) on protein-restricted or control dams. All pups were refed under control conditions following the episode of undernutrition. Before refeeding, and 2, 7 and 21 days later, muscle protein synthesis was measured in vivo. There were no long-term deficits in protein mass in GLP and E-UN offspring, but in L-UN offspring muscle protein mass remained significantly smaller even after 18 months (P < 0.001). E-UN differed from L-UN offspring by their capacity to upregulate postprandial muscle protein synthesis when refed (P < 0.001), a difference that was attributable to a transient increase in ribosomal abundance, i.e. translational capacity, in E-UN offspring (P < 0.05); translational efficiency was similar across dietary treatments. The postprandial phosphorylation of Akt and extracellular signal-regulated protein kinases were similar among treatments. However, activation of the ribosomal S6 kinase 1 via mTOR (P < 0.02), and total upstream binding factor abundance were significantly greater in E-UN than L-UN offspring (P < 0.02). The results indicate that the capacity of muscles to recover following perinatal undernutrition depends on developmental age as this establishes whether ribosome abundance can be enhanced sufficiently to promote the protein synthesis rates required to accelerate protein deposition for catch-up growth.

Skeletal muscle ATP turnover by 31P magnetic resonance spectroscopy during moderate and heavy bilateral knee extension

01 December 2014

During constant-power high-intensity exercise, the expected increase in oxygen uptake (VO2) is supplemented by a VO2 slow component (VO2 sc ), reflecting reduced work efficiency, predominantly within the locomotor muscles. The intracellular source of inefficiency is postulated to be an increase in the ATP cost of power production (an increase in P/W). To test this hypothesis, we measured intramuscular ATP turnover with 31P magnetic resonance spectroscopy (MRS) and whole-body VO2 during moderate (MOD) and heavy (HVY) bilateral knee-extension exercise in healthy participants (n = 14). Unlocalized 31P spectra were collected from the quadriceps throughout using a dual-tuned (1H and 31P) surface coil with a simple pulse-and-acquire sequence. Total ATP turnover rate (ATPtot) was estimated at exercise cessation from direct measurements of the dynamics of phosphocreatine (PCr) and proton handling. Between 3 and 8 min during MOD, there was no discernable VO2 sc (mean ± SD, 0.06 ± 0.12 l min–1) or change in [PCr] (30 ± 8 vs. 32 ± 7 mm) or ATPtot (24 ± 14 vs. 17 ± 14 mm min–1; each P = n.s.). During HVY, the VO2 sc was 0.37 ± 0.16 l min–1 (22 ± 8%), [PCr] decreased (19 ± 7 vs. 18 ± 7 mm, or 12 ± 15%; P < 0.05) and ATPtot increased (38 ± 16 vs. 44 ± 14 mm min–1, or 26 ± 30%; P < 0.05) between 3 and 8 min. However, the increase in ATPtot (ATPtot) was not correlated with the VO2 sc during HVY (r2 = 0.06; P = n.s.). This lack of relationship between ATPtot and VO2 sc , together with a steepening of the [PCr]–VO2 relationship in HVY, suggests that reduced work efficiency during heavy exercise arises from both contractile (P/W) and mitochondrial sources (the O2 cost of ATP resynthesis; P/O).

Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner

01 December 2014
Key points

  • Millions of elderly individuals have dysphagia, a debilitating and life-threatening condition in which the ability to swallow is impaired.

  • Several muscles surround the three regions of the pharynx, which are essential for proper swallowing, yet the effects of ageing and disease on these muscles are not well understood.

  • We demonstrate that the fibre size of murine pharyngeal muscles is differentially affected by ageing and muscular dystrophy depending on their location within the pharynx.

  • Using a mouse model of an age-associated dysphagic disease (oculopharyngeal muscular dystrophy), we show that overexpression of wild-type polyadenylate binding nuclear protein 1 in muscle tissue prevents age-related dysphagia and age-related muscle atrophy of laryngopharyngeal muscles.

  • These results demonstrate that mice are an excellent model for studying mechanisms of ageing and disease on pharyngeal muscle physiology, and such studies could lead to new therapies for individuals with dysphagia.

  • Abstract

    The inability to swallow, or dysphagia, is a debilitating and life-threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild-type mice depending on the particular muscle analysed. Furthermore, wild-type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild-type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild-type A10 PABPN1 was protective against age-related muscle atrophy in the laryngopharynx and prevented the development of age-related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region-dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia.

    Endothelial nitric oxide synthase mediates the nitric oxide component of reflex cutaneous vasodilatation during dynamic exercise in humans

    01 December 2014

    Recent data suggests neuronal nitric oxide synthase (nNOS) mediates the NO component of reflex cutaneous vasodilatation with passive heat stress. We tested the hypothesis that nNOS inhibition would attenuate reflex cutaneous vasodilatation during sustained dynamic exercise in young healthy humans. All subjects first performed an incremental VO2, peak test to exhaustion on a custom-built supine cycle ergometer. On a separate day, subjects were instrumented with four intradermal microdialysis fibres on the forearm and each randomly assigned as: (1) lactated Ringer's (control); (2) 20 mm N-nitro-l-arginine methyl ester hydrochloride (non-selective NOS inhibitor); (3) 5 mm N-propyl-l-arginine (nNOS inhibitor); and (4) 10 mm N5-(1-iminoethyl)-l-ornithine dihydrochloride [endothelial NOS (eNOS) inhibitor]. Following microdialysis placement, subjects performed supine cycling with the experimental arm at heart level at 60% VO2, peak for a period sufficient to raise core temperature 0.8°C. At the end of cycling, all microdialysis sites were locally heated to 43°C and sodium nitroprusside was perfused to elicit maximal vasodilatation. Mean arterial pressure, skin blood flow via laser-Doppler flowmetry and core temperature via ingestible telemetric pill were measured continuously; cutaneous vascular conductance (CVC) was calculated as laser-Doppler flowmetry/mean arterial pressure and normalized to maximum. There was no significant difference between control (58 ± 2%CVCmax) and nNOS-inhibited (56 ± 3%CVCmax) sites in response to exercise-induced hyperthermia. The increase in CVC at eNOS-inhibited (41 ± 3%CVCmax) and non-selective NOS-inhibited (40 ± 4%CVCmax) sites were significantly attenuated compared to control and nNOS-inhibited (P < 0.001 all conditions) but there was no difference between eNOS-inhibited and non-selective NOS-inhibited sites. These data suggest eNOS, not nNOS, mediate NO synthesis during reflex cutaneous vasodilatation with sustained dynamic exercise.

    Evidence for cyclooxygenase-dependent sweating in young males during intermittent exercise in the heat

    01 December 2014
    Key points

  • Previous studies implicate nitric oxide (NO) in the control of sweating during exercise in the heat; however, it is unclear whether cyclooxygenase (COX) is also involved.

  • We demonstrated that exercise-induced sweating at a moderate heat production (400 W, ~40% VO2 max ) was similarly reduced when COX and NO synthase were inhibited separately and in combination.

  • Alternatively, inhibiting COX and/or NO synthase did not influence exercise-induced sweating at a high heat production (700 W, ~70% VO2 max ).

  • We show that both COX and NO are involved in sweating during exercise at moderate heat production and that the effects may not be independent. However, roles for COX and NO are less evident when heat production is elevated.

  • The results lead to better understanding of the mechanisms of sweating and indicate that COX inhibitors (e.g. aspirin) may impair core body temperature regulation and thereby increase the risk of heat-related illness.

  • Abstract

    Our recent work implicated nitric oxide (NO) in the control of sweating during intermittent exercise; however, it is unclear if cyclooxygenase (COX) is also involved. On separate days, ten healthy young (24 ± 4 years) males cycled in the heat (35°C). Two 30 min exercise bouts were performed at either a moderate (400 W, moderate heat load) or high (700 W, high heat load) rate of metabolic heat production and were followed by 20 and 40 min of recovery, respectively. Forearm sweating (ventilated capsule) was evaluated at four skin sites that were continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control), (2) 10 mm ketorolac (a non-selective COX inhibitor), (3) 10 mm NG-nitro-l-arginine methyl ester (l-NAME; a non-selective NO synthase inhibitor) or (4) a combination of 10 mm ketorolac + 10 mm l-NAME. During the last 5 min of the first exercise at moderate heat load, forearm sweating (mg min–1 cm–2) was equivalently reduced with ketorolac (0.54 ± 0.08), l-NAME (0.55 ± 0.07) and ketorolac+l-NAME (0.56 ± 0.08) compared to Control (0.67 ± 0.06) (all < 0.05). Similar results were obtained for the second exercise at moderate heat load (all < 0.05). However, forearm sweating was similar between the four sites during exercise at high heat load and during recovery regardless of exercise intensity (all > 0.05). We show that (1) although both COX and NO modulate forearm sweating during intermittent exercise bouts in the heat at a moderate heat load, the effects are not additive, and (2) the contribution of both enzymes to forearm sweating is less evident during intermittent exercise when the heat load is high and during recovery.

    Wiring patterns in the mouse retina: collecting evidence across the connectome, physiology and light microscopy

    15 November 2014

    The visual system has often been thought of as a parallel processor because distinct regions of the brain process different features of visual information. However, increasing evidence for convergence and divergence of circuit connections, even at the level of the retina where visual information is first processed, chips away at a model of dedicated and distinct pathways for parallel information flow. Instead, our current understanding is that parallel channels may emerge, not from exclusive microcircuits for each channel, but from unique combinations of microcircuits. This review depicts diagrammatically the current knowledge and remaining puzzles about the retinal circuit with a focus on the mouse retina. Advances in techniques for labelling cells and genetic manipulations have popularized the use of transgenic mice. We summarize evidence gained from serial electron microscopy, electrophysiology and light microscopy to illustrate the wiring patterns in mouse retina. We emphasize the need to explore proposed retinal connectivity using multiple methods to verify circuits both structurally and functionally.

    Resurgent current of voltage-gated Na+ channels

    15 November 2014

    Resurgent Na+ current results from a distinctive form of Na+ channel gating, originally identified in cerebellar Purkinje neurons. In these neurons, the tetrodotoxin-sensitive voltage-gated Na+ channels responsible for action potential firing have specialized mechanisms that reduce the likelihood that they accumulate in fast inactivated states, thereby shortening refractory periods and permitting rapid, repetitive, and/or burst firing. Under voltage clamp, step depolarizations evoke transient Na+ currents that rapidly activate and quickly decay, and step repolarizations elicit slower channel reopening, or a ‘resurgent’ current. The generation of resurgent current depends on a factor in the Na+ channel complex, probably a subunit such as NaVβ4 (Scn4b), which blocks open Na+ channels at positive voltages, competing with the fast inactivation gate, and unblocks at negative voltages, permitting recovery from an open channel block along with a flow of current. Following its initial discovery, resurgent Na+ current has been found in nearly 20 types of neurons. Emerging research suggests that resurgent current is preferentially increased in a variety of clinical conditions associated with altered cellular excitability. Here we review the biophysical, molecular and structural mechanisms of resurgent current and their relation to the normal functions of excitable cells as well as pathophysiology.