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PubMed2005

Disease mechanisms in hereditary sensory and autonomic neuropathies.

Inherited peripheral neuropathies are common monogenically inherited diseases of the peripheral nervous system. In the most common variant, i.e., the hereditary motor and sensory neuropathies, both motor and sensory nerves are affected. In contrast, sensory abnormalities predominate or are exclusively present in hereditary sensory and autonomic neuropathies (HSAN). HSAN are clinically and genetically heterogeneous and are subdivided according to mode of inheritance, age of onset and clinical evolution. In recent years, 6 disease-causing genes have been identified for autosomal dominant and recessive HSAN. However, vesicular transport and axonal trafficking seem important common pathways leading to degeneration of sensory and autonomic neurons. This review discusses the HSAN-related genes and their biological role in the disease mechanisms leading to HSAN.

Animals↗
PubMed2004

CHLOROPLAST BIOGENESIS genes act cell and noncell autonomously in early chloroplast development.

In order to identify nuclear genes required for early chloroplast development, a collection of photosynthetic pigment mutants of Arabidopsis was assembled and screened for lines with extremely low levels of chlorophyll. Nine chloroplast biogenesis (clb) mutants that affect proplastid growth and thylakoid membrane formation and result in an albino seedling phenotype were identified. These mutations identify six new genes as well as a novel allele of cla1. clb mutants have less than 2% of wild-type chlorophyll levels, and little or no expression of nuclear and plastid-encoded genes required for chloroplast development and function. In all but one mutant, proplastids do not differentiate enough to form elongated stroma thylakoid membranes. Analysis of mutants during embryogenesis allows differentiation between CLB genes that act noncell autonomously, where partial maternal complementation of chloroplast development is observed in embryos, and those that act cell autonomously, where complementation during embryogenesis is not observed. Molecular characterization of the noncell autonomous clb4 mutant established that the CLB4 gene encodes for hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase (HDS), the next to the last enzyme of the methylerythritol 4-phosphate (MEP) pathway for the synthesis of plastidic isoprenoids. The noncell autonomous nature of the clb4 mutant suggests that products of the MEP pathway can travel between tissues, and provides in vivo evidence that some movement of MEP intermediates exists from the cytoplasm to the plastid. The isolation and characterization of clb mutants represents the first systematic study of genes required for early chloroplast development in Arabidopsis.

Arabidopsis↗
PubMed2002

Opsin-G11-mediated signaling pathway for photic entrainment of the chicken pineal circadian clock.

Light is a major environmental signal for entrainment of the circadian clock, but little is known about the intracellular phototransduction pathway triggered by light activation of the photoreceptive molecule(s) responsible for the phase shift of the clock in vertebrates. The chicken pineal gland and retina contain the autonomous circadian oscillators together with the photic entrainment pathway, and hence they represent useful experimental models for the clock system. Here we show the expression of G11alpha, an alpha subunit of heterotrimeric G-protein, in both tissues by cDNA cloning, Northern blot, and Western blot analyses. G11alpha immunoreactivity was colocalized with pinopsin in the chicken pineal cells and also with rhodopsin in the outer segments of retinal photoreceptor cells, suggesting functional coupling of G11alpha with opsins in the clock-containing photosensitive tissues. The physical interaction was examined by coimmunoprecipitation experiments, the results of which provided evidence for light- and GTP-dependent coupling between rhodopsin and G11alpha. To examine whether activation of endogenous G11 leads to a phase shift of the oscillator, Gq/11-coupled m1-type muscarinic acetylcholine receptor (mAChR) was ectopically expressed in the cultured pineal cells. Subsequent treatment of the cells with carbamylcholine (CCh), an agonist of mAChR, induced phase-dependent phase shifts of the melatonin rhythm in a manner very similar to the effect of light. In contrast, CCh treatment induced no measurable effect on the rhythm of nontransfected (control) cells or cells expressing G(i/o)-coupled m2-type mAChR, indicating selectivity of the G-protein activation. Together, our results demonstrate the existence of a G11-mediated opsin-signaling pathway contributing to the photic entrainment of the circadian clock.

Animals↗
PubMed2006

The cerebellar-hypothalamic circuits: potential pathways underlying cerebellar involvement in somatic-visceral integration.

The cerebellum has been considered only as a classical subcortical center for motor control. However, accumulating experimental and clinical evidences have revealed that the cerebellum also plays an important role in cognition, for instance, in learning and memory, as well as in emotional behavior and in nonsomatic activities, such as visceral and immunological responses. Although it is not yet clear through which pathways such cerebellar nonsomatic functions are mediated, the direct bidirectional connections between the cerebellum and the hypothalamus, a high autonomic center, have recently been demonstrated in a series of neuroanatomical investigations on a variety of mammals and indicated to be potential pathways underlying the cerebellar autonomic modulation. The direct hypothalamocerebellar projections originate from the widespread hypothalamic nuclei/areas and terminate in both the cerebellar cortex as multilayered fibers and the cerebellar nuclei. Immunohistochemistry studies have offered fairly convincing evidence that some of these projecting fibers are histaminergic. It has been suggested that through their excitatory effects on cerebellar cortical and nuclear cells mediated by metabotropic histamine H(2) and/or H(1) receptors, the hypothalamocerebellar histaminergic fibers participate in cerebellar modulation of somatic motor as well as non-motor responses. On the other hand, the direct cerebellohypothalamic projections arise from all cerebellar nuclei (fastigial, anterior and posterior interpositus, and dentate nuclei) and reach almost all hypothalamic nuclei/areas. Neurophysiological and neuroimaging studies have demonstrated that these connections may be involved in feeding, cardiovascular, osmotic, respiratory, micturition, immune, emotion, and other nonsomatic regulation. These observations provide support for the hypothesis that the cerebellum is an essential modulator and coordinator for integrating motor, visceral and behavioral responses, and that such somatic-visceral integration through the cerebellar circuitry may be fulfilled by means of the cerebellar-hypothalamic circuits.

Animals↗
PubMed1997

The enzymic potential of tissue kallikrein (rK1) in rat submandibular saliva depends on whether it was secreted via constitutive or regulated pathways.

The enzymic activity and immunoreactivity of rat tissue kallikrein (rK1) secreted at rest by granular duct cells of unstimulated submandibular glands has been compared with that secreted on autonomic nerve stimulation. Although a direct vesicular, constitutive secretory pathway operates for rK1 secretion from granular duct cells of unstimulated and parasympathetically stimulated glands the rK1 was not present in a pro-form and actually showed a greater enzymic activity per unit immunoreactive protein than the granule-derived rK1 in sympathetically evoked saliva. Constitutively secreted rK1 was found to be in a single chain molecular form by reducing SDS gel electrophoresis. In contrast rK1 secreted from the storage granule pool of granular duct cells on sympathetic nerve stimulation was present in much higher amounts and occurred in both one-chain and two-chain forms as revealed by SDS gel electrophoresis under reducing conditions. The lower enzymic potential of rK1 in sympathetically evoked saliva might be accounted for by its conversion to a two-chain form.

Animals↗
PubMed1994

Nitric oxide--a novel autonomic neurotransmitter.

Considerable evidence suggests that nitric oxide (NO) acts as a nonadrenergic noncholinergic (NANC) transmitter at autonomic neuroeffector junctions. NO is generated enzymatically from L-arginine by a constitutive, cytosolic, Ca2+/calmodulin-activated NO synthase (NOS): NADPH- and tetrahydrobiopterin-dependent cytochrome P-450-type hemoprotein. Electrophysiological and pharmacological data indicate that NO fulfils most of the criteria for a neurotransmitter. It is released from axon terminals when invaded by action potentials and mimics the effect of nerve stimulation. The changes in the mechanical and/or electrical activity of smooth muscle preparations in response to transmural stimulation of NANC nerves are antagonized by inhibitors of NO synthesis or oxyhemoglobin, an NO scavenger. NO acts principally by stimulating soluble guanylate cyclase. Studies on the histochemical localization of NOS point to the involvement of the neural L-arginine-NO pathway in the regulation of vascular tone and of several aspects of respiratory, gastrointestinal, and genitourinary tract functions.

Animals↗
PubMed1998

The suprachiasmatic nucleus-paraventricular nucleus interactions: a bridge to the neuroendocrine and autonomic nervous system.

Vasopressin (VP) is one of the principal neurotransmitters of the suprachiasmatic nucleus (SCN). By means of anatomical, physiological and electrophysiological techniques we have demonstrated that VP containing pathways from the SCN serve to affect neuroendocrine and 'autonomic' neurons in the paraventricular nucleus. By direct and indirect connections VP serves to inhibit corticosterone secretion, not only by affecting ACTH secretion but also by controlling the adrenal cortex via a neuronal route. Apart from controlling the pineal and adrenal, we also observed that the SCN is able to influence the heart. Subjecting rats or humans to light affects heart rate in a dose-dependent manner. These results suggest an important role for the SCN and VP in the SCN in the regulation of neuroendocrine and autonomic functions.

Animals↗
PubMed1984

Spinal sympathetic pathway: an enkephalin ladder.

Enkephalin distribution was examined in autonomic areas of the rat thoracic spinal cord. The localization of enkephalin fibers coincided with nuclear regions containing sympathetic preganglionic neurons. Horizontal sections revealed a pattern for enkephalin fibers resembling Laruelle's description of the localization of sympathetic preganglionic neurons as rungs of a ladder.

Animals↗
PubMed2000

Descending projections of infralimbic cortex that mediate stimulation-evoked changes in arterial pressure.

The infralimbic cortex (IL) of the rat can modify autonomic nervous system activity, but the critical pathway(s) that mediate this influence are unclear. To define the potential pathways, the first series of experiments characterizes the descending projections of IL and the neighboring cortical areas using Phaseolus vulgaris leucoagglutinin (PHA-L). IL has prominent projections to the central nucleus of the amygdala (Ce), the mediodorsal nucleus of the thalamus (MD), the lateral hypothalamic area (LHA), the periaqueductal gray (PAG), the parabrachial nucleus (Pb), and the nucleus of the solitary tract (NTS). The density and selectivity of these projections suggest that the LHA and the PAG mediate the ability of the IL to regulate cardiovascular function. The second series of experiments demonstrates that locally anesthetizing neurons in either the LHA or PAG with lidocaine attenuates the hypotensive effects produced by electrical stimulation of the IL. Similarly, microinjections of cobalt chloride (a neurotransmission blocker) into the anterior portion of the LHA also decrease the arterial pressure responses to IL stimulation, suggesting that the ability of lidocaine to reversibly block the evoked response is due to inactivation of neurons in the LHA. These data indicate that hypotension evoked by stimulation of IL is mediated, at least in part, by direct or indirect projections to the LHA and through the PAG.

Animals↗
PubMed2004

Alexithymia predicts attenuated autonomic reactivity, but prolonged recovery to anger recall in young women.

Alexithymia has been prospectively associated with all-cause mortality and with cardiovascular morbidity. Here, stress-induced autonomic reactivity and recovery were examined as potential pathways linking alexithymia to cardiovascular disease. The relation of alexithymia to blood pressure, heart rate, and other cardiovascular parameters derived from impedance cardiography (N = 80) and heart rate variability (N = 40) was evaluated during rest, an anger recall task and recovery in women (ages 18-30). During anger recall, alexithymia was associated with significantly attenuated heart rate and stroke index reactivity, greater low frequency power, and with marginally dampened blood pressure and high frequency power reactivity. Overall, this response pattern suggests blunted sympathetic activation and diminished vagal withdrawal. Alexithymia was also related to slower diastolic blood pressure and quicker preejection period recovery implying abbreviated sympathetic arousal and possibly greater vagal modulation. These results impart some evidence for the hypoarousal model of alexithymia during reactivity, but the hyperarousal model during recovery. Autonomic dysregulation during and following acute emotional stress is suggested as a possible physiological pathway connecting alexithymia to cardiovascular disease.

Adult↗
PubMed2002

A subclass of plant heat shock cognate 70 chaperones carries a motif that facilitates trafficking through plasmodesmata.

Plasmodesmata establish a pathway for the trafficking of non-cell-autonomously acting proteins and ribonucleoprotein complexes. Plasmodesmal enriched cell fractions and the contents of enucleate sieve elements, in the form of phloem sap, were used to isolate and characterize heat shock cognate 70 (Hsc70) chaperones associated with this cell-to-cell transport pathway. Three Cucurbita maxima Hsc70 chaperones were cloned and functional and sequence analysis led to the identification of a previously uncharacterized subclass of non-cell-autonomous chaperones. The highly conserved nature of the heat shock protein 70 (Hsp70) family, in conjunction with mutant analysis, permitted the characterization of a motif that allows these Hsc70 chaperones to engage the plasmodesmal non-cell-autonomous translocation machinery. Proof of concept that this motif is necessary for Hsp70 gain-of-movement function was obtained through the engineering of a human Hsp70 that acquired the capacity to traffic through plasmodesmata. These results are discussed in terms of the roles likely played by this subclass of Hsc70 chaperones in the trafficking of non-cell-autonomous proteins.

Amino Acid Motifs↗
PubMed1993

Cardiovascular autonomic dysfunction in multiple sclerosis is likely related to brainstem lesions.

Impairment of cardiovascular autonomic reflexes has been described in multiple sclerosis (MS), and believed reflecting dysfunction of reflex pathways located within the central nervous system. A battery of cardiovascular autonomic tests were performed in 40 patients with definite MS: R-R interval variation test, deep breathing, Valsalva manoeuvre, blood pressure and heart rate responses to standing, sustained handgrip. The results were evaluated by Bayesian analysis, a pattern recognition technique. The patients had also magnetic resonance imaging (MRI) of brain and in 19 subjects of cervical spinal cord. Deep breathing test and sustained handgrip test produced most frequently abnormal results (17.5% and 40%, respectively). However, only 4 patients (10% had two or more tests abnormal, with a very variable pattern. Evaluation by Bayesian analysis revealed 7 patients (17.5%) with definite autonomic dysfunction. A correlation was found between the confidence level obtained by Bayesian analysis, as index of autonomic function, and the Kurtzke brainstem FS score (r = 0.43, P < 0.01). There was a significant association between presence of autonomic dysfunction and clinical (P < 0.02) and MRI (P < 0.005) evidence of brainstem lesions.

Adult↗
PubMed1994

Neural and biochemical mediators of endotoxin and stress-induced c-fos expression in the rat brain.

We and others have reported that c-fos protein is induced in the hypothalamus and brain stem of the rat following central and peripheral injections of endotoxin (lipopolysaccharide; LPS). We have now examined possible mechanisms through which LPS induces c-fos protein. The cyclooxygenase inhibitor indomethacin and the glutamate NMDA antagonist MK801 inhibited c-fos protein in the paraventricular nucleus (PVN), supraoptic nucleus (SON), and the A1/A2 regions of the brain stem induced by IP or IV injections of LPS (40 micrograms). The H1 histamine antagonist diphenhydramine, but not the H2 histamine antagonist cimetidine, reduced the amount of c-fos labeling. MK801 also attenuated the effects of stress (foot shock) on c-fos protein; however, indomethacin had no effect on c-fos protein induced by stress. We next examined the importance of visceral afferent innervation on the response to LPS or stress. Subdiaphragmatic vagotomy completely blocked the induction of c-fos protein following IP injections of LPS; however, vagotomy had a minimal effect on c-fos protein induced in the PVN and SON following IV injections of LPS, but potentiated c-fos induction following foot shock. Thus, prostaglandin synthesis, glutamate release, histamine receptors, and visceral afferents represent functional biochemical and neural pathways through which endotoxin activates c-fos protein in specific autonomic and neuroendocrine regulatory nuclei. Activation of NMDA glutamate receptors may represent a final common pathway for the induction of c-fos protein in the brain induced by both endotoxin and stress.

Animals↗
PubMed2006

Defining the transcriptome of accelerated and replicatively senescent keratinocytes reveals links to differentiation, interferon signaling, and Notch related pathways.

Epidermal keratinocytes (KCs) undergo highly orchestrated morphological and molecular changes during transition from proliferative compartment into growth arrested early and late differentiation layers, prior to dying in outermost cornified layers of normal skin. Creation of stratum corneum is vital to barrier function protecting against infection. Transcriptional events in KCs regulating complex processes of differentiation and host defense required to maintain constant epidermal thickness and resistance to infection in either young or aged skin are largely unknown. Furthermore, as terminal differentiation is characterized by irreversible loss of replicative potential culminating in dead layers at the skin surface, this process may be viewed as a form of senescence. However, a complete transcriptional profile of senescent (SN) human KCs has not been previously defined to permit delineation of molecular boundaries involving differentiation and senescence. To fill this void, we utilized global transcriptional analysis of KCs maintained in vitro as either cultures of proliferating (PR) cells, early and late confluent (LC) (accelerated senescence) cultures, or KCs undergoing replicative senescence. Global gene expression profiling revealed early confluent (EC) KCs were somewhat similar to PR KCs, while prominent differences were evident when compared to LC KCs; which were also distinct from replicatively SN KCs. While confluent KCs have in common several genes regulating differentiation with replicatively SN KCs, the latter cells expressed elevated levels of genes involved in interferon signaling and inflammatory pathways. These results provide new insights into cell autonomous transcriptional-based programs operative within KCs contributing to replicative senescence, with partial sharing of genes involved in differentiation. In addition, regulation of KC senescence may involve participation of interferon signaling pathways derived from the important role of KCs in protecting skin from infection. Integrating all of the transcriptional data revealed a key role for Notch receptor mediated signaling in the confluency induced differentiation phenotype using this model system.

Apoptosis↗
PubMed1999

Uremic autonomic neuropathy studied by spectral analysis of heart rate.

BACKGROUND: There is good evidence that power spectral analysis (PSA) of heart rate variability may provide an insight into the understanding of autonomic disorders. METHODS: We investigated 30 chronic uremic patients who were on periodic bicarbonate hemodialysis by a battery of six cardiovascular autonomic tests (beat-to-beat variations during quiet breathing and deep breathing, heart rate responses to the Valsalva maneuver and standing, blood pressure responses to standing and sustained handgrip) and PSA of heart rate variations. RESULTS: Eleven patients (37%) had an abnormal response to only one parasympathetic test. Twelve patients (40%) had a definite parasympathetic damage, as indicated by at least two abnormal heart rate tests, whereas four (13%) had combined parasympathetic and sympathetic damage. Multivariate analysis of the cardiovascular tests revealed that 19 patients (63%) had moderate-to-severe autonomic neuropathy (AN), and 11 patients exhibited normal autonomic function. Among the symptoms suggestive of autonomic dysfunction, only impotence in males was significantly associated with test-proven AN. The PSA of the heart rate variability demonstrated a good discrimination of low-frequency (LF) and high-frequency (HF) bands (LF, 0.03 to 0.15 Hz; HF, 0.15 to 0.33 Hz) among controls, uremic patients without test-proven AN, and uremic patients with test-proven AN. A significant reduction of the LF value on supine uremic patients without AN suggests that an early sympathetic involvement exists that traditional autonomic tests were unable to detect. CONCLUSIONS: Our study indicates that the current opinion of a major parasympathetic damage in chronic uremic patients on hemodialysis has to be modified in favor of a more widespread autonomic dysfunction involving both the sympathetic and parasympathetic pathways.

Adult↗
PubMed2005

Estrogen signaling in the hypothalamus.

Estrogen has multifaceted effects on the hypothalamus that regulate a number of homeostatic functions including reproduction, temperature, energy balance, stress, and motivated behaviors. Estrogen targets all of the major hypothalamic neuroendocrine and autonomic cellular groups to activate multiple signaling pathways. Originally it was thought that all of these actions of estrogen could be ascribed to its binding to its "classical" intracellular receptor and to alterations in gene transcription. However, we now know that this steroid hormone activates multiple signaling pathways to affect neuronal excitability and gene transcription. Although the "classical" genomic signaling pathway has been recognized for almost half a century, until recently little attention has been paid to the rapid membrane-initiated signaling by estrogen in neurons. It has been known since the 1970s that estrogen can rapidly alter neuronal firing within seconds, indicating that some cellular effects of estrogen could occur via rapid, non-transcriptional mechanisms. Therefore, this chapter reviews the current status of estrogen signaling in the hypothalamus via membrane-initiated and nuclear-mediated events that affect the excitability of hypothalamic neurons and, ultimately, neuroendocrine and autonomic functions.

Animals↗
PubMed2006

The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells.

The mitogen-activated protein kinase (MAPK) pathway is frequently activated in human cancers, leading to malignant phenotypes such as autonomous cellular proliferation. Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation. The suppressive activity of the culture supernatants from the melanoma cells on the production of inflammatory cytokines IL-12 and tumor necrosis factor alpha by dendritic cells upon lipopolysaccharide stimulation was markedly reduced after transduction with BRAF(V600E) RNAi, comparable to the effects observed with STAT3 RNAi transduction. No additive or synergistic effects were observed by the simultaneous transduction of RNAi for both BRAF(V600E) and STAT3. Furthermore, specific DNA binding and transcriptional activity of STAT3 were not affected by down-regulation of the MAPK signaling with the BRAF RNAi. These results indicate that the MAPK signal, along with the STAT3 signal, is essential for immune evasion by human melanomas that have constitutively active MAPK signaling and is a potential molecular target for overcoming melanoma cell evasion of the immune system.

Cell Line, Tumor↗