SUMMARY Lipid rafts are specialized membrane microdomains that function as signaling platforms across plasma membranes of many animal and plant cells. Although there are several studies implicating the role of lipid rafts in capacitation of mammalian sperm, the function of these structures in sperm motility activation and chemotaxis remains unknown. In the ascidian Ciona intestinalis, egg-derived sperm activating- and attracting-factor (SAAF) induces both activation of sperm motility and sperm chemotaxis to the egg. Here we found that a lipid raft disrupter, methyl-b-cyclodextrin (MCD), inhibited both SAAF-induced sperm motility activation and chemotaxis. MCD inhibited both SAAF-promoted synthesis of intracellular cyclic AMP and sperm motility induced by ionophore-mediated Ca2þ entry, but not that induced by valinomycin-mediated hyperpolarization. Ca2þ-imaging revealed that lipid raft disruption inhibited Ca2þ influx upon activation of sperm motility. The Ca2þ-activated adenylyl cyclase was clearly inhibited by MCD in isolated lipid rafts. The results suggest that sperm lipid rafts function in signaling upstream of cAMP synthesis, most likely in SAAF-induced Ca2þ influx, and are required for Ca2þ-dependent pathways underlying activation and chemotaxis in Ciona sperm.

Background: Spinal synaptic plasticity may contribute to paclitaxel-induced painful neuropathy. Results: Paclitaxel treatment impairs GABA-mediated neuronal inhibition and increases total and plasma membrane NKCC1 protein levels in the spinal cord. Blocking NKCC1 reverses paclitaxel effects on synaptic inhibition and pain hypersensitivity. Conclusion: Paclitaxel diminishes synaptic inhibition in the spinal cord. Significance: This study demonstrates how disrupting microtubule dynamics causes synaptic plasticity and neuropathic pain.

Duchenne muscular dystrophy is a lethal genetic disease of muscle wasting for which there is no cure. In healthy muscle, structure and function improve dramatically with exercise. In patients with dystrophy, little is known about the effects of exercise. As contemporary therapies rapidly progress and patients become more active, there is a need to understand the effects of exercise.

Endothelium-dependent vasodilation is reduced after acute exercise or after high intraluminal pressure in isolated arterioles from sedentary adults but not in arterioles from regular exercisers. The preserved vasodilation in arterioles from exercisers is hydrogen peroxide (H2O2) dependent, whereas resting dilation is nitric oxide (NO) dependent. We hypothesize chronic exercise elicits adaptations allowing for maintained vasodilation when NO bioavailability is reduced.

Marrow mesenchymal stem cells supply bone osteoblasts and adipocytes. Exercise effects to increase bone and decrease fat involve transfer of signals from the cytoplasm into the nucleus to regulate gene expression. We propose that exercise control of stem cell fate relies on structural connections that terminate in the nucleus and involve intranuclear actin structures that regulate epigenetic gene expression.

Exercise and pharmacologic therapies to prevent and treat cardiovascular disease have advanced largely through independent efforts. Understanding of first-line drug therapies, findings from preclinical animal studies, and the need for research initiatives related to complementary cardioprotective exercise-pharma interventions are reviewed from the premise that contemporary cardioprotective therapies must include adjunctive exercise and lifestyle interventions in addition to pharmacologic agents.

The presence of mechanical linkages between synergistic muscles and their common tendons may distribute forces among the involved structures. We review studies, using humans and other animals, examining muscle and tendon interactions and discuss the hypothesis that connections between muscle bellies and within tendons may serve as a mechanism to distribute forces and mitigate peak stresses.

An imbalance in oxygen delivery to demand in solid tumors results in local areas of hypoxia leading to poor prognosis for the patient. We hypothesize that aerobic exercise increases tumor blood flow, recruits previously nonperfused tumor blood vessels, and thereby augments blood-tumor O2 transport and diminishes tumor hypoxia. When combined with conventional anticancer treatments, aerobic exercise can significantly improve the outcomes for several types of cancers.

The hypothalamic paraventricular nucleus (PVN) is critically involved in elevated sympathetic output and the development of hypertension. However, changes in group I metabotropic glutamate receptors (mGluR1 and mGluR5) and their relevance to the hyperactivity of PVN presympathetic neurons in hypertension remain unclear. Here, wefoundthat selectively blocking mGluR5 significantly reducedthe basal firing activity of spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs), but not in normotensive WistarKyoto (WKY) rats. However, blocking mGluR1 had no effect onthe firing activity of PVN neurons in either group. The mRNA and protein levels of mGluR5 in the PVN and rostral ventrolateral medulla were significantly higher in SHRs than in WKY rats. The group I mGluR selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) similarly increased the firing activity of PVN neurons in WKY rats and SHRs. In addition, blocking NMDA receptors (NMDARs)through bath application or intracellular dialysis not only decreasedthe basal firing in SHRs, but also eliminated DHPG-induced excitation of spinally projecting PVN neurons. DHPG significantly increased the amplitude of NMDAR currents without changing their decay kinetics. Interestingly, DHPG still increased the amplitude of NMDAR currents and caused reappearance of functional NMDAR channels after initially blocking NMDARs. In addition, protein kinase C (PKC) inhibition or intracellular dialysis with synaptosomal-associated protein of 25 kDa (SNAP-25)-blocking peptide abolished DHPG-induced increases in NMDAR currents of PVN neurons in SHRs. Our findings suggest that mGluR5 in the PVN is upregulated in hypertension and contributes to the hyperactivity of PVN presympathetic neurons through PKC- and SNAP-25-mediated surface expression of NMDARs.

Lipid rafts are specialized membrane microdomains that function as signaling platforms across plasma membranes of many animal and plant cells. Although there are several studies implicating the role of lipid rafts in capacitation of mammalian sperm, the function of these structures in sperm motility activation and chemotaxis remains unknown. In the ascidian Ciona intestinalis, egg-derived sperm activating- and attracting-factor (SAAF) induces both activation of sperm motility and sperm chemotaxis to the egg. Here we found that a lipid raft disrupter, methyl-b-cyclodextrin (MCD), inhibited both SAAF-induced sperm motility activation and chemotaxis. MCD inhibited both SAAF-promoted synthesis of intracellular cyclic AMP and sperm motility induced by ionophore-mediated Ca2þ entry, but not that induced by valinomycin-mediated hyperpolarization. Ca2þ-imaging revealed that lipid raft disruption inhibited Ca2þ influx upon activation of sperm motility. The Ca2þ-activated adenylyl cyclase was clearly inhibited by MCD in isolated lipid rafts. The results suggest that sperm lipid rafts function in signaling upstream of cAMP synthesis, most likely in SAAF-induced Ca2þ influx, and are required for Ca2þ-dependent pathways underlying activation and chemotaxis in Ciona spe

SUMMARY Lipid rafts are specialized membrane microdomains that function as signaling platforms across plasma membranes of many animal and plant cells. Although there are several studies implicating the role of lipid rafts in capacitation of mammalian sperm, the function of these structures in sperm motility activation and chemotaxis remains unknown. In the ascidian Ciona intestinalis, egg-derived sperm activating- and attracting-factor (SAAF) induces both activation of sperm motility and sperm chemotaxis to the egg. Here we found that a lipid raft disrupter, methyl-b-cyclodextrin (MCD), inhibited both SAAF-induced sperm motility activation and chemotaxis. MCD inhibited both SAAF-promoted synthesis of intracellular cyclic AMP and sperm motility induced by ionophore-mediated Ca2þ entry, but not that induced by valinomycin-mediated hyperpolarization. Ca2þ-imaging revealed that lipid raft disruption inhibited Ca2þ influx upon activation of sperm motility. The Ca2þ-activated adenylyl cyclase was clearly inhibited by MCD in isolated lipid rafts. The results suggest that sperm lipid rafts function in signaling upstream of cAMP synthesis, most likely in SAAF-induced Ca2þ influx, and are required for Ca2þ-dependent pathways underlying activation and chemotaxis in Ciona sperm.

Background: Spinal synaptic plasticity may contribute to paclitaxel-induced painful neuropathy. Results: Paclitaxel treatment impairs GABA-mediated neuronal inhibition and increases total and plasma membrane NKCC1 protein levels in the spinal cord. Blocking NKCC1 reverses paclitaxel effects on synaptic inhibition and pain hypersensitivity. Conclusion: Paclitaxel diminishes synaptic inhibition in the spinal cord. Significance: This study demonstrates how disrupting microtubule dynamics causes synaptic plasticity and neuropathic pain.

Duchenne muscular dystrophy is a lethal genetic disease of muscle wasting for which there is no cure. In healthy muscle, structure and function improve dramatically with exercise. In patients with dystrophy, little is known about the effects of exercise. As contemporary therapies rapidly progress and patients become more active, there is a need to understand the effects of exercise.

Endothelium-dependent vasodilation is reduced after acute exercise or after high intraluminal pressure in isolated arterioles from sedentary adults but not in arterioles from regular exercisers. The preserved vasodilation in arterioles from exercisers is hydrogen peroxide (H2O2) dependent, whereas resting dilation is nitric oxide (NO) dependent. We hypothesize chronic exercise elicits adaptations allowing for maintained vasodilation when NO bioavailability is reduced.

Marrow mesenchymal stem cells supply bone osteoblasts and adipocytes. Exercise effects to increase bone and decrease fat involve transfer of signals from the cytoplasm into the nucleus to regulate gene expression. We propose that exercise control of stem cell fate relies on structural connections that terminate in the nucleus and involve intranuclear actin structures that regulate epigenetic gene expression.

Exercise and pharmacologic therapies to prevent and treat cardiovascular disease have advanced largely through independent efforts. Understanding of first-line drug therapies, findings from preclinical animal studies, and the need for research initiatives related to complementary cardioprotective exercise-pharma interventions are reviewed from the premise that contemporary cardioprotective therapies must include adjunctive exercise and lifestyle interventions in addition to pharmacologic agents.

The presence of mechanical linkages between synergistic muscles and their common tendons may distribute forces among the involved structures. We review studies, using humans and other animals, examining muscle and tendon interactions and discuss the hypothesis that connections between muscle bellies and within tendons may serve as a mechanism to distribute forces and mitigate peak stresses.

An imbalance in oxygen delivery to demand in solid tumors results in local areas of hypoxia leading to poor prognosis for the patient. We hypothesize that aerobic exercise increases tumor blood flow, recruits previously nonperfused tumor blood vessels, and thereby augments blood-tumor O2 transport and diminishes tumor hypoxia. When combined with conventional anticancer treatments, aerobic exercise can significantly improve the outcomes for several types of cancers.

The hypothalamic paraventricular nucleus (PVN) is critically involved in elevated sympathetic output and the development of hypertension. However, changes in group I metabotropic glutamate receptors (mGluR1 and mGluR5) and their relevance to the hyperactivity of PVN presympathetic neurons in hypertension remain unclear. Here, wefoundthat selectively blocking mGluR5 significantly reducedthe basal firing activity of spinally projecting PVN neurons in spontaneously hypertensive rats (SHRs), but not in normotensive WistarKyoto (WKY) rats. However, blocking mGluR1 had no effect onthe firing activity of PVN neurons in either group. The mRNA and protein levels of mGluR5 in the PVN and rostral ventrolateral medulla were significantly higher in SHRs than in WKY rats. The group I mGluR selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) similarly increased the firing activity of PVN neurons in WKY rats and SHRs. In addition, blocking NMDA receptors (NMDARs)through bath application or intracellular dialysis not only decreasedthe basal firing in SHRs, but also eliminated DHPG-induced excitation of spinally projecting PVN neurons. DHPG significantly increased the amplitude of NMDAR currents without changing their decay kinetics. Interestingly, DHPG still increased the amplitude of NMDAR currents and caused reappearance of functional NMDAR channels after initially blocking NMDARs. In addition, protein kinase C (PKC) inhibition or intracellular dialysis with synaptosomal-associated protein of 25 kDa (SNAP-25)-blocking peptide abolished DHPG-induced increases in NMDAR currents of PVN neurons in SHRs. Our findings suggest that mGluR5 in the PVN is upregulated in hypertension and contributes to the hyperactivity of PVN presympathetic neurons through PKC- and SNAP-25-mediated surface expression of NMDARs.

Lipid rafts are specialized membrane microdomains that function as signaling platforms across plasma membranes of many animal and plant cells. Although there are several studies implicating the role of lipid rafts in capacitation of mammalian sperm, the function of these structures in sperm motility activation and chemotaxis remains unknown. In the ascidian Ciona intestinalis, egg-derived sperm activating- and attracting-factor (SAAF) induces both activation of sperm motility and sperm chemotaxis to the egg. Here we found that a lipid raft disrupter, methyl-b-cyclodextrin (MCD), inhibited both SAAF-induced sperm motility activation and chemotaxis. MCD inhibited both SAAF-promoted synthesis of intracellular cyclic AMP and sperm motility induced by ionophore-mediated Ca2þ entry, but not that induced by valinomycin-mediated hyperpolarization. Ca2þ-imaging revealed that lipid raft disruption inhibited Ca2þ influx upon activation of sperm motility. The Ca2þ-activated adenylyl cyclase was clearly inhibited by MCD in isolated lipid rafts. The results suggest that sperm lipid rafts function in signaling upstream of cAMP synthesis, most likely in SAAF-induced Ca2þ influx, and are required for Ca2þ-dependent pathways underlying activation and chemotaxis in Ciona spe