Do polymorphisms in the human 5-HT3 genes contribute to pathological phenotypes?

5-HT3 receptors are members of the Cys-loop superfamily of ligand-gated ion channels. In both the central and the peripheral nervous systems, 5-HT3 receptors excite postsynaptic cells and modulate the release of neurotransmitters from presynaptic neurons. 5-HT3 receptors are known to be involved in mediation of nausea/emesis caused by chemo/radio-therapy and anaesthesia, and more recently have also been found to be involved in irritable bowel syndrome. 5-HT3 receptors have also been suggested to play a role in a range of other indications, including various psychiatric disorders. This review summarizes the current evidence for the contribution of 5-HT3 subunit genes to disease phenotypes arising from association studies. Furthermore, it suggests how in vitro characterization of naturally occurring genetic variants can be used to obtain a better understanding of the causal relationship between gene and disease.

Glutamine supplementation further enhances exercise-induced plasma IL-6.

Exercise stimulates the production and release of interleukin-6 (IL-6) from skeletal muscle. Glutamine is also synthesized in skeletal muscle and is involved in protein synthesis within this tissue. During exercise, plasma levels of glutamine decline, and this may affect the concentration of plasma IL-6 via a decrease in IL-6 synthesis and release from muscle. We hypothesized that glutamine supplementation would attenuate the exercise-induced decrease in plasma glutamine concentration and, thus, further enhance levels of plasma IL-6. Eight healthy men participated in a randomized, double-blind, crossover study in which they performed 2 h of cycle ergometry at 75% of peak O2 uptake. They received glutamine, glutamine-rich protein, or placebo supplementation at intervals during and 2 h after exercise. Exercise induced an 11-fold increase in plasma IL-6, which was further enhanced by glutamine (18-fold) and glutamine-rich protein (14-fold) supplementation, administered at doses that attenuated the exercise-induced decrease in plasma glutamine concentration.

Effect of glutamine supplementation on exercise-induced changes in lymphocyte function.

The purpose of this study was to investigate the possible role of glutamine in exercise-induced impairment of lymphocyte function. Ten male athletes participated in a randomized, placebo-controlled, double-blind crossover study. Each athlete performed bicycle exercise for 2 h at 75% of maximum O(2) consumption on 2 separate days. Glutamine or placebo supplements were given orally during and up to 2 h postexercise. The trial induced postexercise neutrocytosis that lasted at least 2 h. The total lymphocyte count increased by the end of exercise due to increase of both CD3(+)TCR alpha beta(+) and CD3(+)TCR gamma delta(+) T cells as well as CD3(-)CD16(+)CD56(+) natural killer (NK) cells. Concentrations of CD8(+) and CD4(+) T cells lacking CD28 and CD95 on their surface increased more than those of cells expressing these receptors. Within the CD4(+) cells, only CD45RA(-) memory cells, but not CD45RA(+) naive cells, increased in response to exercise. Most lymphocyte subpopulations decreased 2 h after exercise. Glutamine supplementation abolished the postexercise decline in plasma glutamine concentration but had no effect on lymphocyte trafficking, NK and lymphokine-activated killer cell activities, T cell proliferation, catecholamines, growth hormone, insulin, or glucose. Neutrocytosis was less pronounced in the glutamine-supplemented group, but it is unlikely that this finding is of any clinical significance. This study does not support the idea that glutamine plays a mechanistic role in exercise-induced immune changes.

Effect of glutamine and protein supplementation on exercise-induced decreases in salivary IgA.

Postexercise immune impairment has been linked to exercise-induced decrease in plasma glutamine concentration. This study examined the possibility of abolishing the exercise-induced decrease in salivary IgA through glutamine supplementation during and after intense exercise. Eleven athletes performed cycle ergometer exercise for 2 h at 75% of maximal oxygen uptake on 3 separate days. Glutamine (a total of 17.5 g), protein (a total of 68.5 g/6.2 g protein-bound glutamine), and placebo supplements were given during and up to 2 h after exercise. Unstimulated, timed saliva samples were obtained before exercise and 20 min, 140 min, 4 h, and 22 h postexercise. The exercise protocol induced a decrease in salivary IgA (IgA concentration, IgA output, and IgA relative to total protein). The plasma concentration of glutamine was decreased by 15% 2 h postexercise in the placebo group, whereas this decline was abolished by both glutamine and protein supplements. None of the supplements, however, was able to abolish the decline in salivary IgA. This study does not support that postexercise decrease in salivary IgA is related to plasma glutamine concentrations.

Cytokines in aging and exercise.

Aging is associated with increased inflammatory activity. Increased plasma levels of tumour necrosis factor (TNF)-alpha were found in centenarians aged 100 years and in individuals aged 80-81 years when compared to a young control group. Plasma levels of TNF-alpha were linearly correlated to plasma levels of interleukin (IL)-6, TNF-receptors and C-reactive protein. High levels of TNF-alpha were directly related to dementia and to a low blood pressure ankle-arm index, indicating generalized atherosclerosis. In hospitalized patients with Streptococcus pneumonia infection, aging was associated with prolonged inflammatory activity. Similar results were found using an in vivo endotoxin challenge model in old versus young humans. Strenuous exercise induces increased levels in a number of proinflammatory and anti-inflammatory cytokines, naturally occurring cytokine inhibitors and chemokines. Thus, increased plasma levels of TNF-alpha, IL-1, IL-6, IL-1 receptor antagonist (IL-Ira), TNF-receptors (TNF-R), IL-10, IL-8 and macrophage inflammatory protein (MIP)-1 are found after strenuous exercise. The cytokine response to strenuous exercise has similarities to the cytokine response to trauma and sepsis. Therefore, in future studies, exercise is suggested as an ethically applicable model to use in studies on mechanisms underlying the age-associated altered cytokine response.

Exercise and immune function: effect of ageing and nutrition.

Strenuous exercise is followed by lymphopenia, neutrophilia, impaired natural immunity, decreased lymphocyte proliferative responses to mitogens, a low level of secretory immunoglobulin A in saliva, but high circulating levels of pro- and anti-inflammatory cytokines. These exercise-induced immune changes may provide the physiological basis of altered resistance to infections. The mechanisms underlying exercise-induced immune changes are multifactorial and include neuroendocrinological and metabolic mechanisms. Nutritional supplementation with glutamine abolishes the exercise-induced decline in plasma glutamine, but does not influence post-exercise immune impairment. However, carbohydrate loading diminishes most exercise effects of cytokines, lymphocyte and neutrophils. The diminished neutrophilia and elastase (EC 3.4.21.37) responses to eccentric exercise in elderly subjects were enhanced to levels comparable with those of young subjects by fish oil or vitamin E supplements. However, although vitamin C supplementation may diminish the risk of contracting an infection after strenuous exercise, it is not obvious that this effect is linked to an effect of vitamin C on exercise-induced immune changes. In conclusion, it is premature to make recommendations regarding nutritional supplementation to avoid post-exercise impairment of the immune system.

Glutamine, exercise, and the immune system--is there a link?

Glutamine is known to be important for cells replicating in culture. It has been proposed that the decrease in plasma glutamine concentration in relation to catabolic conditions, including strenuous exercise, resulting in a lack of glutamine for cells of the immune system, is responsible for the transient postexercise immunosuppression. This review discusses the potential role of glutamine on the postexercise in-vitro changes in immune parameters. Furthermore, the value of glutamine as a nutritional supplement to athletes and the possible influence on these parameters is reviewed.