Gating current harmonics. III. Dynamic transients and steady states with intact sodium inactivation gating.

Internally perfused squid giant axons with intact sodium inactivation gating were prepared for gating current experiments. Gating current records were obtained in sinusoidally driven dynamic steady states and as dynamic transients as functions of the mean membrane potential and the frequency of the command sinusoid. Controls were obtained after internal protease treatment of the axons that fully removed inactivation. The nonlinear analysis consisted of determining and interpreting the harmonic content in the current records. The results indicate the presence of three kinetic processes, two of which are associated with activation gating (the so-called primary and secondary processes), and the third with inactivation gating. The dynamic steady state data show that inactivation gating does not contribute a component to the gating current, and has no direct voltage-dependence of its own. Rather, the inactivation kinetics appear to be coupled to the primary activation kinetics, and the coupling mechanism appears to be one of reciprocal steric hindrance between two molecular components. The mechanism allows the channel to become inactivated without first entering the conducting state, and will do so in about 40 percent of depolarizing voltage-clamp steps to 0 mV. The derived model kinetics further indicate that the conducting state may flicker between open and closed with the lifetime of either state being 10 microseconds. Dynamic transients generated by the model kinetics (i.e., the behavior of the harmonic components as a function of time after an instantaneous change in the mean membrane potential from a holding potential of -80 mV) match the experimental dynamic transients in all details. These transients have a duration of 7-10 ms (depending on the level of depolarization), and are the result of the developing inactivation following the discontinuous voltage change. A detailed hypothetical molecular model of the channel and gating machinery is presented.     

Focus: Addiction: Video Game Use in the Treatment of Amblyopia: Weighing the Risks of Addiction

Video games have surged in popularity due to their entertainment factor and, with recent innovation, their use in health care. This review explores the dual facets of video games in treating vision impairment in amblyopia as well as their potential for overuse and addiction. Specifically, this review examines video game addiction from a biopsychosocial perspective and relates the addictive qualities of video games with their use as a therapeutic treatment for amblyopia. Current literature supports both the identification of video game addiction as a disease, as well as the therapeutic potential of video games in clinical trials. We show the need for clinicians to be aware of the dangers associated with video game overuse and the need for future studies to examine the risks associated with their health care benefits.     

Vertebrate sickness behaviors: Adaptive and integrated neuroendocrine immune responses

Vertebrate sickness behaviors, which include lethargy, anorexia, and decreased libido, can facilitate defense against pathogens by conserving energy for use in other immune responses and by limiting parasites' access to nutrients. Such benefits come with considerable costs, however, as lethargy decreases the time available for other fitness-enhancing activities and dampened libido directly reduces reproductive prospects. While the degree of sickness behaviors expressed varies among individuals, populations, and species, the ecological and physiological factors driving this diversity remain unclear. Here, we consider how an organism's ecological context and life-history strategy may impact the ways in which it balances the costs and benefits of sickness behaviors to enable or suppress its expression. Striking an appropriate balance requires physiological assimilation of information about external ecological conditions as well as about the status of infection and host nutrition. This integration requires multi-directional communication among the endocrine, nervous, and immune systems, the purview of the field of psychoneuroimmunology. This discipline portrays cytokines, signaling molecules originally characterized solely by their roles within the immune system, as key mediators of a brain-immune network that ensures the adaptive expression of sickness behaviors. Study of these molecules and the behaviors they coordinate in an ecological context will greatly augment our understanding of the natural variation in immune function found among wild animals.     

Sensing muscle ischemia: coincident detection of acid and ATP via interplay of two ion channels

Ischemic pain--examples include the chest pain of a heart attack and the leg pain of a 30 s sprint--occurs when muscle gets too little oxygen for its metabolic need. Lactic acid cannot act alone to trigger ischemic pain because the pH change is so small. Here, we show that another compound released from ischemic muscle, adenosine tri-phosphate (ATP), works together with acid by increasing the pH sensitivity of acid-sensing ion channel number 3 (ASIC3), the molecule used by sensory neurons to detect lactic acidosis. Our data argue that ATP acts by binding to P2X receptors that form a molecular complex with ASICs; the receptor on sensory neurons appears to be P2X5, an electrically quiet ion channel. Coincident detection of acid and ATP should confer sensory selectivity for ischemia over other conditions of acidosis.     

Repulsion between tetraethylammonium ions in cloned voltage-gated potassium channels.

Tetraethylammonium ion (TEA+) blocks voltage-gated K+ channels by acting at two sites located at opposite ends of the aqueous pore. This allowed us to test two predictions made by models of ion permeation, namely that K+ channels can be simultaneously occupied by multiple ions and that the ions repel each other. We show that externally applied TEA+ antagonize block by internal TEA+ and vice versa. The antagonism is less than predicted for competitive binding, hence TEA+ may occupy both sites simultaneously. External TEA+ and internal TEA+ reduce each others affinity 4- to 5-fold. In addition, K+ antagonizes block by TEA+ at the opposite side of the membrane, and external TEA+ antagonizes is block by internal Ba2+. The antagonism between ions applied at opposite sides of the membrane may be common to all cations binding to K+ channels.