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PubMed1994

DIFFERENTIAL TRACER COUPLING BETWEEN PAIRS OF IDENTIFIED NEURONES OF THE MOLLUSC LYMNAEA STAGNALIS

Electrical coupling is a common means of cell-to-cell communication in both neuronal and non-neuronal tissues (Lowenstein, 1985). Within the nervous system, many electrically coupled neurones exhibit dye coupling (Bennett, 1973; Stewart, 1978; Glantz and Kirk, 1980; Spencer and Satterlie, 1980; Fraser and Heitler, 1993); however, some electrically coupled cells do not dye-couple (Audesirk et al. 1982; Murphy et al. 1983; Berdan, 1987; Robinson et al. 1993; Veenstra et al. 1993). Electrical coupling and dye coupling, often considered in parallel, are in fact two different parameters that can vary independently (e.g. Audesirk et al. 1982; Perez-Armendariz et al. 1991). The giant identified neurones of pulmonate and opisthobranch molluscs have frequently been used for studies of neuronal communication and its plasticity (Winlow and McCrohan, 1987; Bulloch, 1989). In the present study, we explored the relationship between electrical and tracer coupling in both strongly and weakly coupled pairs of molluscan neurones. Specifically, we examined electrically coupled, identified neurones in a freshwater pond snail, Lymnaea stagnalis L., and tested for tracer coupling with Lucifer Yellow CH and biocytin. The cells examined were the strongly electrically coupled neurones, visceral dorsal 1 (VD1) and right parietal dorsal 2 (RPD2) (Boer et al. 1979; Benjamin and Pilkington, 1986), and the weakly coupled neurones, left buccal 1 (LB1) and right buccal 1 (RB1) (Benjamin and Rose, 1979). The use of these particular neurones made it possible to compare electrical coupling with tracer coupling in the molluscan central nervous system (CNS). All experiments were performed on laboratory-bred Lymnaea stagnalis (Mollusca, Pulmonata), maintained as previously described (Ridgway et al. 1991). The CNS was dissected from mature animals (1618 mm shell length) and pinned to the silicone rubber (RTV 616 GE) base of a recording dish in normal saline (51.3 mmol l-1 NaCl, 1.7 mmol l-1 KCl, 4.1 mmol l-1 CaCl2, 1.5 mmol l-1 MgCl2 and 5 mmol l-1 Hepes, pH 7.9). Following removal of the outer connective tissue sheath, a small Pronase crystal (Sigma, type XIV, P-5147), held by forceps, was carefully applied to specific ganglia; this treatment softened the inner sheath and facilitated microelectrode penetration. The CNS was then rinsed several times at 5 °C in normal saline.

Journal Article↗

PubMed1983

Axotomy-induced parallel increases in electrical and dye coupling between identified neurons of Helisoma.

The electrically coupled buccal ganglion neurons 4R and 4L of the snail, Helisoma, display predictable plasticity. The strength of the electronic synapse between them increases significantly following axotomy. Synaptic strength was assayed by measurements of electrical coupling coefficients and by assessment of dye coupling (passage of dye into the uninjected neuron) following injection of Lucifer Yellow CH into one neuron. Within 3 to 5 days, axotomy induced an increase in electrical coupling coefficients between neurons 4R and 4L from 0.54 +/- 0.11 (n = 13) in normal preparations to 0.72 +/- 0.14 (n = 24). A parallel axotomy-induced increase in the probability of dye coupling occurred. Only 27% (n = 27) of normal neuron 4 pairs were dye coupled, compared with 87% (n = 15) of axotomized neuronal pairs. Irrespective of treatment, electrical and dye measurements in the same neuron 4 pairs showed a consistent correlation between the magnitude of the electrical coupling coefficients and the probability of detectable dye coupling. No dye coupling was observed in neuronal pairs with electrical coupling coefficients less than 0.50. Dye coupling always occurred when coupling coefficients were greater than 0.70. Sixty-seven percent of neuronal pairs with intermediate coupling (0.50 to 0.70) coefficients displayed dye coupling. The results show that axotomy evokes a predictable enhancement of communication at an "identified" electronic synapse and suggests that electrical and dye coupling are mediated by similar mechanisms.

Animals↗

PubMedDate not supplied

A comparison of receptive field and tracer coupling size of horizontal cells in the rabbit retina.

The large receptive fields of retinal horizontal cells are thought to reflect extensive electrical coupling via gap junctions. It was shown recently that the biotinylated tracers, biocytin and Neurobiotin, provide remarkable images of coupling between many types of retinal neuron, including horizontal cells. Further, these demonstrations of tracer coupling between horizontal cells rivaled the size of their receptive fields, suggesting that the pattern of tracer coupling may provide some index of the extent of electrical coupling. We studied this question by comparing the receptive field and tracer coupling size of dark-adapted horizontal cells recorded in the superfused, isolated retina-eyecup of the rabbit. Both the edge-to-edge receptive field and space constants (lambda) were computed for each cell using a long, narrow slit of light displaced across the retinal surface. Cells were subsequently labeled by iontophoretic injection of Neurobiotin. The axonless A-type horizontal cells showed extensive, homologous tracer coupling in groups greater than 1000 covering distances averaging about 2 mm. The axon-bearing B-type horizontal cells were less extensively tracer coupled, showing homologous coupling of the somatic endings in groups of about 100 cells spanning approximately 400 microns and a separate homologous coupling of the axon terminal endings covering only about 275 microns. Moreover, we observed a remarkable, linear relationship between the size of the receptive fields of each of the three horizontal cell endings and the magnitude of their tracer coupling. Our findings suggest that the extent of tracer coupling provides a strong, linear index of the magnitude of electrical current flow, as derived from receptive-field measures, across groups of coupled horizontal cells. These data thus provide the first direct evidence that the receptive-field size of horizontal cells is related to the extent of their coupling via gap junctions.

Animals↗

PubMed2002

Investigation of the mechanisms of G protein: effector coupling by the human and mouse prostacyclin receptors. Identification of critical species-dependent differences.

We recently identified a novel mechanism explaining how the mouse (m) prostacyclin receptor (IP) couples to Galpha(s), Galpha(i), and Galpha(q) (Lawler, O. A., Miggin, S. M., and Kinsella, B. T. (2001) J. Biol. Chem. 276, 33596-33607) whereby mIP coupling to Galpha(i) and Galpha(q) is dependent on its initial coupling to Galpha(s) and subsequent phosphorylation by cAMP-dependent protein kinase A (PKA) on Ser(357). In the current study, the generality of that mechanism was investigated by examining the G protein coupling specificity of the human (h) IP. The hIP efficiently coupled to Galpha(s)/adenylyl cyclase and to Galpha(q)/phospholipase C activation but failed to couple to Galpha(i). Coupling of the hIP to Galpha(q), or indeed to Galpha(s) or Galpha(i), was unaffected by the PKA or protein kinase C (PKC) inhibitors H-89 and GF 109203X, respectively. Thus, mIP and hIP exhibit essential differences in their coupling to Galpha(i) and in their dependence on PKA in regulating their coupling to Galpha(q). Analysis of their primary sequences revealed that the critical PKA phosphorylation site within the mIP, at Ser(357), is replaced by a PKC site within the hIP, at Ser(328). Conversion of the PKC site of the hIP to a PKA site generated hIP(QL325,326RP) that efficiently coupled to Galpha(s) and to Galpha(i) and Galpha(q); coupling of hIP(QL325,326RP) to Galpha(i) but not to Galpha(s) or Galpha(q) was inhibited by H-89. Abolition of the PKC site of the hIP generated hIP(S328A) that efficiently coupled to Galpha(s) and Galpha(q) but failed to couple to Galpha(i). Finally, conversion of the PKA site at Ser(357) within the mIP to a PKC site generated mIP(RP354,355QL) that efficiently coupled to Galpha(s) but not to Galpha(i) or Galpha(q). Collectively, our data highlight critical differences in signaling by the mIP and hIP that are regulated by their differential phosphorylation by PKA and PKC together with contextual sequence differences surrounding those sites.

Amino Acid Sequence↗

PubMed2000

Repeating the errors of our parents? Family-of-origin spouse violence and observed conflict management in engaged couples.

Based on a developmental social learning analysis, it was hypothesized that observing parental violence predisposes partners to difficulties in managing couple conflict. Seventy-one engaged couples were assessed on their observation of parental violence in their family of origin. All couples were videotaped discussing two areas of current relationship conflict, and their cognitions during the interactions were assessed using a video-mediated recall procedure. Couples in which the male partner reported observing parental violence (male-exposed couples) showed more negative affect and communication during conflict discussions than couples in which neither partner reported observing parental violence (unexposed couples). Couples in which only the female partner reported observing parental violence (female-exposed couples) did not differ from unexposed couples in their affect or behavior. Female-exposed couples reported more negative cognitions than unexposed couples, but male-exposed couples did not differ from unexposed couples in their reported cognitions.

Adult↗

PubMed1996

Influence of histocompatibility antigens in recurrent spontaneous abortion couples and on their reproductive performances.

PROBLEM: To determine if human leukocyte antigens (HLA) play any role in the aetiology of recurrent spontaneous abortion (RSA), a substantial group of RSA couples were studied, and their reproductive performances in a 3-year follow-up recorded. METHODS: HLA typing was performed for HLA-A, -B, and DR antigens in both partners of 75 couples with unexplained RSA, and compared with a control group of 30 fertile couples that never experienced abortion. A further 57 couples of this group were studied for their reproductive performance in a 3-year follow-up, and subdivided into three subgroups: 1) couples that achieved successful pregnancy during the follow-up, and subdivided into three subgroups: 1) couples that achieved successful pregnancy during the follow-up; 2) couples that experienced abortion and no livebirth during the follow-up; and 3) couples that experienced infertility during the follow-up. RESULTS: There were no significant differences for antigen frequency in all the different HLA loci, and HLA antigen sharing between all the RSA couples and controls. Significant increase of sharing for HLA-DR locus was observed in the couples that aborted during the follow-up with respect to the couples that achieved livebirth and controls (P < 0.03 and P < 0.02 respectively), and significantly increased frequency of B44, DR5 antigen combination in the same comparison (P < 0.03). No significant differences were observed in terms of the interval between conceptions in couples without antigen sharing with respect to couples with 1, 2 or more antigens shared, and antigen sharing in Locus A, B or DR. CONCLUSIONS: The results suggest that gene(s) disadvantageous for reproduction may exist between the HLA-B and -DR chromosomal region which influences the pregnancy outcome in RSA couples, and that HLA-antigen sharing itself does not influence the outcome.

Abortion, Habitual↗

PubMedDate not supplied

Coupling efficiencies of amino acids in the solid phase synthesis of peptides.

The "classical" Merrifield method was used to synthesize over 500 peptides using Boc-benzyl strategy. The peptides were prepared either manually or on a Beckman 990B synthesizer or an Applied Biosystems 430A synthesizer. Each coupling of Boc amino acid to the growing peptide on the resin was monitored with the ninhydrin reaction. Couplings were considered "incomplete" if there was 99% or less coupling and "high incomplete" if there was 98% or less coupling. The efficiency of coupling was evaluated in regard to the specific amino acids involved in the coupling reaction and to the length of the peptide at the time of the coupling. The most difficult carboxyl-reacting amino acids were histidine, threonine, arginine, valine, isoleucine and glutamine; the most difficult amine reacting residues were glutamine, leucine, alanine, arginine and isoleucine. The number of "incomplete" and "high incomplete" couplings and the total number of monitored couplings of each of the 20 carboxyl-reacting amino acids when reacting with each of the 20 amine-reacting residues were tabulated. Coupling efficiencies decreased with the length of the peptide. The conclusion of this study is that, with the chemistries and methods used in this group of peptides, no amino acid coupling can be predicted to be complete with a single coupling reaction. The study points to the need for on-line determination of coupling efficiency during the synthesis in which a recoupling step is initiated when the first coupling is incomplete.

Amino Acids↗

PubMed1987

Dye-coupling in taste buds in the mudpuppy, Necturus maculosus.

Electrical coupling in taste buds and in non-taste lingual epithelium in the mudpuppy was examined by injecting cells with a fluorescent dye, Lucifer yellow. Lucifer yellow coupling has been shown to indicate the presence of electrical junctions between cells. Lucifer yellow-filled taste cells usually have an elongate shape. Cells were an average of 111 microns long and were 13 microns in diameter at the widest region (nucleus). In taste buds, from a sample of 105 impalements we detected Lucifer yellow coupling in 21 cases: dye-coupled pairs of cells were observed in 17 cases, and trios of cells in 4 cases. Larger subsets of coupled cells (greater than 3) were not observed. Dye-coupled cells were usually equally intensely stained. In non-taste epithelium, we examined dye-coupling in the superficial and basal layers. Extensive Lucifer yellow coupling was found in the basal layer (15/15 cases). The number of cells coupled to the dye-injected cell varied from 3 to 5. In the superficial epithelium, dye-coupling was rare (1/45 cases). No dye-coupling was observed between epithelial cells and taste cells at the taste pore region. We conclude that strong electrical coupling in groups of 2-3 cells occurs in the mudpuppy taste buds. Coupling may occur selectively between identical types of taste cells (dark, light, etc.), but this remains to be determined. Electrical coupling also exists among basal epithelial cells but not in the superficial epithelial layers.

Animals↗

PubMed1999

Couple-responsible therapy process: positive proximal outcomes.

Therapist-couple struggle vs. cooperation is linked to clinical outcome. This research conceptualizes and investigates treatment process as it relates to the occurrence of struggle versus cooperation. Models of couple-responsible and therapist-responsible process in couple therapy were developed. Couple-responsible process consists of enactments, accommodation, and inductive process. Therapist-responsible process consists of primary therapist-couple interaction, therapist interpretation, and direct instruction. In counterbalanced order, 25 couples were exposed to couple-responsible and therapist-responsible episodes during one therapy session. Couples reviewed videotapes of the episodes and completed measures of responsibility, struggle, and cooperation. Perceived responsibility was higher and struggle was lower during couple-responsible episodes. No difference in cooperation was found. Presence or absence of a contrast condition, where couples reported on one therapist process after already experiencing its opposite, led to main effects for responsibility and struggle, and mediated effects of struggle and cooperation. Generally speaking, responsibility was even higher during couple-responsible episodes and even lower during therapist-responsible episodes when contrast was present. Similarly, struggle was even lower during couple-responsible episodes and even higher during therapist-responsible episodes when contrast was present. For both couple-responsible and therapist-responsible episodes, cooperation was negatively affected by a shift from the prior, opposite therapist process. Significant proportions of the variance in responsibility, struggle, and cooperation, however, were not accounted for by therapist process alone.

Adult↗

PubMed1999

Coordination of spinal locomotor activity in the lamprey: long-distance coupling of spinal oscillators.

The extent and strength of long-distance coupling between locomotor networks in the rostral and caudal spinal cord of larval lamprey were examined with in vitro brain/spinal cord preparations, in which spinal locomotor activity was initiated by chemical microstimulation in the brain, as well as with computer modeling. When locomotor activity and short-distance coupling were blocked in the middle spinal cord for at least 40 segments, burst activity in the rostral and caudal spinal cord was still coupled 1:1, indicating that long-distance coupling is extensive. However, in the absence of short-distance coupling, intersegmental phase lags were not constant but decreased significantly with increasing cycle times, suggesting that long-distance coupling maintains a relatively constant delay rather than a constant phase lag between rostral and caudal bursts. In addition, under these conditions, intersegmental phase lags, measured between rostral and caudal burst activity, were significantly less than normal, and the decrease was greater for longer distances between rostral and caudal locomotor networks. The above result could be mimicked by a computer model consisting of pairs of oscillators in the rostral, middle, and caudal spinal cord that were connected by short- and long-distance coupling. With short-distance coupling blocked in the middle spinal cord, strychnine was applied to either the rostral or caudal spinal cord to convert the pattern locally from right-left alternation to synchronous burst activity. Synchronous burst activity in the rostral spinal cord resulted in a reduction in right-left phase values for burst activity in the caudal cord. These results also could be mimicked by the computer model. Strychnine-induced synchronous burst activity in the caudal spinal cord did not appear to alter the right-left phase values of rostral burst activity. Taken together, the experimental and modeling results suggest that the descending and ascending components of long-distance coupling, although producing qualitatively different effects, are comparatively weak. In particular, the descending component of long-distance coupling appears to become progressively weaker with increasing distance between two given regions of spinal cord. Therefore, short-distance coupling probably contributes substantially to normal rostrocaudal phase lags for locomotor activity along the spinal cord. However, short-distance coupling may be more extensive than "nearest neighbor coupling."

Animals↗

PubMed1985

Dye-coupled magnocellular peptidergic neurons of the rat paraventricular nucleus show homotypic immunoreactivity.

Magnocellular neurons in rat hypothalamic slices are known to exhibit dye coupling: the transfer of the fluorescent dye, Lucifer Yellow, from an intracellularly-injected neuron to one or more nearby neurons. The question of the hormonal identity of coupled cells and the possibility of dye coupling as an artefact led us to determine the immunoreactivity of dye-coupled magnocellular neurons in the paraventricular nucleus of the rat hypothalamus using antisera to oxytocin- and vasopressin-associated neurophysins. In 23 pairs, one triplet, and one quadruplet, immunoreactivity to one or the other antiserum was always exclusive, and dye coupling was always homotypic, that is, coupled neurons in each instance were reactive to the same antiserum. The quadruplet, triplet and 17 pairs were immunoreactive to vasopressin-associated neurophysin, and oxytoxin-associated neurophysin immunoreactivity was observed in the remaining pairs. Immunoreactivity to each antiserum was found for somasomatic and non somasomatic modes of coupling and for coupled neurons in the three magnocellular areas of the nucleus. A relationship between mode of coupling and hormone content was not detected. The data support the hypothesis that coupling is a real, functionally significant mechanism for coordinating neuronal activity in this nucleus, particularly under conditions of high hormone demand. They do not support the idea that coupling is artefact. The possibility of a relationship between hormone content and mode of coupling, and the projection pathway(s) of the coupled neurons of each type require further study.

Animals↗

PubMed2006

Air pockets trapped during routine coupling in dry head lithotripsy can significantly decrease the delivery of shock wave energy.

PURPOSE: Current lithotriptors use a dry treatment head that must be coupled to the patient with gel or oil. We determined how the quality of coupling affects stone breakage under conditions that simulated patient treatment. MATERIALS AND METHODS: Experiments were performed with a Dornier (DoLi-50 electromagnetic lithotriptor. The test tank had a clear Mylar membrane for coupling with the treatment head water cushion. Thus, air pockets trapped at the coupling interface could be photographed for quantitation. Coupling efficiency was assessed using a fiberoptic hydrophone and different coupling regimes were tested for the effect on gypsum stone breakage. RESULTS: The quality of coupling was variable with air pockets covering 1.5% to 19% of the coupling area, resulting in a mean decrease in shock wave amplitude of approximately 20%. Breaking and reestablishing contact, as when a patient is repositioned during treatment, decreased acoustic pressure almost 32%, representing a 57% decrease in acoustic energy transmission. Stone breakage was also decreased when air was trapped in coupling and only 2% coverage by air pockets decreased stone breakage by 20% to 40%. CONCLUSIONS: These in vitro results suggest that coupling in lithotripsy can pose a significant barrier to the transmission of shock wave energy to the patient. Stone breakage was sensitive to air pockets at the coupling interface. Recoupling was particularly disruptive, suggesting that repositioning the patient could substantially degrade coupling quality. It seems reasonable that variability in the quality of coupling could contribute to variability in clinical outcomes.

Air↗

PubMed1998

Pacemaker synchronization of electrically coupled rabbit sinoatrial node cells.

The effects of intercellular coupling conductance on the activity of two electrically coupled isolated rabbit sinoatrial nodal cells were investigated. A computer-controlled version of the "coupling clamp" technique was used in which isolated sinoatrial nodal cells, not physically in contact with each other, were electrically coupled at various values of ohmic coupling conductance, mimicking the effects of mutual interaction by electrical coupling through gap junctional channels. We demonstrate the existence of four types of electrical behavior of coupled spontaneously active cells. As the coupling conductance is progressively increased, the cells exhibit: (a) independent pacemaking at low coupling conductances, (b) complex dynamics of activity with mutual interactions, (c) entrainment of action potential frequency at a 1:1 ratio with different action potential waveforms, and (d) entrainment of action potentials at the same frequency of activation and virtually identical action potential waveforms. The critical value of coupling conductance required for 1:1 frequency entrainment was <0.5 nS in each of the five cell pairs studied. The common interbeat interval at a relatively high coupling conductance (10 nS), which is sufficient to produce entrainment of frequency and also identical action potential waveforms, is determined most by the intrinsically faster pacemaker cell and it can be predicted from the diastolic depolarization times of both cells. Evidence is provided that, at low coupling conductances, mutual pacemaker synchronization results mainly from the phase-resetting effects of the action potential of one cell on the depolarization phase of the other. At high coupling conductances, the tonic, diastolic interactions become more important.

Action Potentials↗

PubMed2006

Molecular determinants in the second intracellular loop of the 5-hydroxytryptamine-1A receptor for G-protein coupling.

This study provides the first comprehensive evidence that the second intracellular loop C-terminal domain (Ci2) is critical for receptor-G protein coupling to multiple responses. Although Ci2 is weakly conserved, its role in 5-hydroxytryptamine-1A (5-HT1A) receptor function was suggested by the selective loss of Gbetagamma-mediated signaling in the T149A-5-HT1A receptor mutant. More than 60 point mutant 5-HT1A receptors in the alpha-helical Ci2 sequence (143DYVNKRTPRR152) were generated. Most mutants retained agonist binding and were tested for Gbetagamma signaling to adenylyl cyclase II or phospholipase C and Galphai coupling to detect constitutive and agonist-induced Gi/Go coupling. Remarkably, most point mutations markedly attenuated 5-HT1A signaling, indicating that the entire Ci2 domain is critical for receptor G-protein coupling. Six signaling phenotypes were observed: wild-type-like, Galphai-coupled/weak Gbetagamma-coupled, Gbetagamma-uncoupled, Gbetagamma-selective coupled, uncoupled, and inverse coupling. Our data elucidate specific roles of Ci2 residues consistent with predictions based on rhodopsin crystal structure. The absolute coupling requirement for lysine, arginine, and proline residues is consistent with a predicted amphipathic alpha-helical Ci2 domain that is kinked at Pro150. Polar residues (Thr149, Asn146) located in the externally oriented positively charged face were required for Gbetagamma but not Galphai coupling, suggesting a direct interface with Gbetagamma subunits. The hydrophobic face includes the critical Tyr144 that directs the specificity of coupling to both Gbetagamma and Galphai pathways. The key coupling residues Tyr144/Lys147 (Ci2) are predicted to orient internally, forming hydrogen and ionic bonds with Asp133/Arg134 (Ni2 DRY motif) and Glu340 (Ci3) to stabilize the Gprotein coupling domain. Thus, the 5-HT1A receptor Ci2 domain determines Gbetagamma specificity and stabilizes Galphai-mediated signaling.

Amino Acid Sequence↗

PubMed2006

Reproductive outcome after chromosome analysis in couples with two or more miscarriages: index [corrected]-control study.

OBJECTIVE: To compare reproductive outcomes in couples carrying a structural chromosome abnormality and non-carrier couples referred for chromosome analysis after two or more miscarriages. DESIGN: Index [corrected]-control study. SETTING: Six centres for clinical genetics in the Netherlands. PARTICIPANTS: 278 carrier couples and 427 non-carrier couples referred for chromosome analysis between 1992 and 2000 after two or more miscarriages before 20 weeks of gestation. Couples were followed up for at least 24 months after chromosome analysis. MAIN OUTCOME MEASURES: The birth of at least one healthy child, at least one more miscarriage, and viable offspring with unbalanced chromosomal abnormalities after parental chromosome analysis. RESULTS: Mean follow-up after chromosome analysis was 5.8 years. 120 of 247 (49%) carrier couples had one or more miscarriage after chromosome analysis compared with 122 of 409 (30%) non-carrier couples (difference 19%, 95% confidence interval 11% to 26%; P < 0.01). The percentage of couples with at least one healthy child was not significantly different in carrier couples (83%) and non-carrier couples (84%) (difference -1%, - 7% to 5%). Among 550 pregnancies in carrier couples, two viable unbalanced chromosome abnormalities were detected at prenatal diagnosis (0.4%) and the fetuses aborted and two children with an unbalanced karyotype were born (0.4%). CONCLUSIONS: Couples whose carrier status was ascertained after two or more miscarriages have a low risk of viable offspring with unbalanced chromosomal abnormalities. Their chances of having a healthy child are as high as non-carrier couples, despite a higher risk of miscarriage.

Abortion, Habitual↗

PubMed1998

The third intracellular loop of the rat gonadotropin-releasing hormone receptor couples the receptor to Gs- and G(q/11)-mediated signal transduction pathways: evidence from loop fragment transfection in GGH3 cells.

The GnRH receptor (GnRH-R) belongs to the rhodopsin/beta-adrenergic family of G protein-coupled receptors. The intracellular domains of these receptors, particularly the regions closest to the plasma membrane in intracellular loops 2 (2i) and 3 (3i) as well as some regions located in the membrane-proximal end of the COOH-terminus, are frequently important sites for G protein coupling and specificity determination. Although studies in mouse and human GnRH-R have identified loop 2i as a critical determinant for coupling the receptor to the G(q/11)-mediated signal transduction pathway, given the functional similarity among the members of this particular G protein-coupled receptor subfamily and the fact that the GnRH-R lacks the typical intracellular COOH-terminal domain of its superfamily (a potential site for G protein coupling), we investigated the possibility that loop 3i of this receptor also participates in GnRH-R coupling to G proteins. GGH(3)1' cells, a pituitary-derived cell line that expresses a functional rat GnRH-R coupled to both Gs and G(q/11) proteins, were transiently transfected with a plasmid DNA containing a complementary DNA (cDNA) coding for the entire loop 3i of the GnRH-R as well as with other expression plasmids containing cDNAs encoding loop 3i of other Gs-, G(i/o)-, or G(q/11)-coupled receptors. The effects of coexpression of these loops with the wild-type GnRH-R on inositol phosphate (IP) production, cAMP accumulation, and PRL release were then examined. Transfection of GGH(3)1' cells with the cDNA for loop 3i of the rat GnRH-R (efficiency, 35-45%) maximally inhibited buserelin-stimulated IP turnover by 20% as well as cAMP accumulation and PRL secretion by 30%. This attenuation in cellular responses to a GnRH agonist was statistically significant (P < 0.05) compared with the responses exhibited by GGH(3)1' cells transfected with a control plasmid and stimulated with the same GnRH agonist. Transfection of minigenes coding for loop 3i of the M1Ach-muscarinic and the alpha1B-adrenergic (G(q/11)-coupled) receptors resulted in 25-55% inhibition of maximal GnRH-evoked IP turnover. Paradoxically, loop 3i from the M1Ach-muscarinic receptor also maximally inhibited GnRH agonist-stimulated cAMP accumulation and PRL release by 40% (both effects mediated through activation of the Gs protein). Transfection of loop 3i from the D1A -dopamine receptor (coupled to the Gs protein) produced a selective attenuation (40%) in Gs-mediated cellular responses. In contrast, receptor/G protein coupling appeared unaffected by expression of loop 3i domains derived from two receptors coupled to G(i/o) proteins (M2Ach-muscarinic and alpha2A-adrenergic receptors). These data indicate that the third intracellular loop of the rat GnRH-R is involved in receptor G(q/11) protein coupling and/or selectivity, and in the GGH(3)1' cell line, this loop is also involved in signal transduction mediated through the Gs protein pathway.

Amino Acid Sequence↗

PubMed1998

Clinical review 100: Evaluation and treatment of the infertile couple.

Infertility by itself does not threaten physical health but has a strong impact on the psychological and social well-being of couples. In the last two decades, progress in caring for the infertile couple, in particular progress in the field of assisted reproduction and micromanipulation, has provided significant hope for many couples for whom hope could not have been offered in the past. This is especially true for bilateral tubal disease and for male factor infertility, as nearly all couples with male factor infertility can now undergo either one (or more) IVF or ICSI attempt(s). For couples with other causes of infertility, however, the differences in pregnancy rates often do not reach statistical significance. We must also remember that the total cost incurred for successful delivery for couples with a better chance of successful IVF (i.e. those with tubal disease) increases from approximately $55,000 in American dollars for the first cycle to $73,000 by the sixth cycle. Because of these high costs, many insurers in the United States and many public health systems in Europe do not cover or only partially cover these procedures. Consequently, the availability of IVF and related therapies frequently depends on the couple's ability to pay. Therefore, after having established the correct diagnosis, appropriate treatment should be counseled to the infertile couple keeping in mind the following points: 1) in subfertile couples expectant management should be reasonably counselled if the age of the woman is less than 30 yr and the duration of infertility is less than 36 months, even if oligozoospermia is present; 2) superovulation and timed intercourse seems also to be a reasonable approach in couples with anovulatory, mild/moderate endometriosis, and unexplained infertility; 3) in unexplained infertility, ovarian stimulation (with clomiphene or gonadotropin) and IUI seem to offer some advantage over ovarian stimulation and timed intercourse; 4) IVF can be a firstline approach in tubal sterility and when IUI or IPI cannot be performed because the number of motile sperm is insufficient, but is usually also the final treatment attempt when other methods have failed. The outcome of IVF is negatively influenced mainly by the woman's age; however, the number of deliveries is also generally lower in couples with male factor; 5) ICSI is a further option, which should be limited to couples: a) with very poor semen parameters; b) previous failed fertilization; c) presence of obstructive or nonobstructive azoospermia in which ICSI is combined with sperm extraction from the epididymis or the testis; 6) international register studies demonstrate that the risk of malformation after conventional IVF is not increased; 7) some reports suggest that incidence of congenital major and minor malformations is not increased in children born after ICSI. However, the rate of sex chromosome anomalies in ICSI fetuses has been reported to be approximately 1% in 585 prenatal diagnoses, a frequency increased by a factor of 4 if compared with naturally conceived live-born babies. ICSI bypasses the physiological selection of spermatozoa that occurs at the level of the testis and epididymis, and in the female reproductive tract as well as at the sperm-oocyte interface. As genetic abnormalities are present in a significant percentage of infertile males with impaired spermatogenesis, karyotyping and analysis of the Y chromosome for microdeletions should be carried out in all potential ICSI fathers. Screening for cystic fibrosis gene mutations should also be performed in azoospermia caused by congenital absence of the vas deferens and seminal vesicles. Appropriate genetic counseling should be made available to all ICSI couples whenever a gene or chromosomal anomaly has been identified. With most ARTs the average delivery rate per cycle is approximately 15% and the cumulative delivery rate after several cycles is about 50%. (ABSTRACT TRUNCATED)

Endocrinology↗

PubMed1995

Balancing our lives: a study of the married couple's experience with breast cancer recurrence.

PURPOSE/OBJECTIVES: To examine the married couple's experience with breast cancer recurrence from each partner's own perspective, to describe their mood and martial quality, and to develop an initial explanatory theory of the couple's lived experience with breast cancer recurrence. DESIGN: Descriptive, qualitative. SETTING: Homes of married couples in the Pacific Northwestern United States. SAMPLES: 15 married couples comprised of women diagnosed with recurrent breast cancer and their husbands. The median length of time since recurrence was 10 months. METHODS: Structured interviews were conducted in the homes of married couples that met eligibility criteria using an open-ended interview schedule, the Marital Dyad Interview, and two standardized questionnaires-the Spanier Dyadic Adjustment Scale and the Center for Epidemiological Studies Depression Scale. MAIN RESEARCH VARIABLES: Lived experience of couples to breast cancer recurrence, depressed mood, and marital adjustment. FINDINGS: BALANCING OUR LIVES was the core category that explained how the couples lived with the breast cancer recurrence. Couples actively worked to balance their lives by keeping the breast cancer a background, not a foreground, issue. Although couples talked about managing the daily realities of the woman's breast cancer, not dwelling on the cancer and moving ahead and healing themselves was most important. Balancing Our Lives involved the couples in four major processes: managing the woman's everyday illness, surviving, healing, and preparing for death. Concurrently, one or both members of 60% of the couples scored outside the normative range on either depressed mood or marital adjustment. CONCLUSIONS: The couples' ways of managing the breast cancer recurrence through balancing their lives may be facilitating their behavioral functioning but may not be enhancing their mood or marital quality. IMPLICATIONS FOR NURSING PRACTICE: The couples' management of recurrence may benefit from additional strategies, including helping them work through sad thoughts or feelings instead of avoiding them; recognizing and supporting each other's views, even when their views differ; and helping them to learn ways to express sad thoughts and feelings without overly dwelling on them.

Adaptation, Psychological↗