Multiple α1-adrenergic receptor subtypes support synergistic stimulation of vasopressin and oxytocin release by ATP and phenylephrine

Simultaneous exposure of explants of the hypothalamo-neurohypophyseal system (HNS) to ATP and the α1-adrenergic receptor (α1-R) agonist, phenylephrine (ATP+PE) induces a synergistic stimulation of vasopressin and oxytocin (VP/OT) release that is sustained for hours ( 23 ). The current studies confirm that the synergism is dependent upon activation of α1-R by demonstrating that an α1-R antagonist prevents the response. The role of the α1A, B, and D-adrenergic receptor subtypes in the synergistic effect of ATP+PE on intracellular calcium ([Ca2+]i) in supraoptic nucleus (SON) neurons and VP/OT release from neural lobe was evaluated. The increase in [Ca2+]i induced by PE in SON predominantly reflects release from intracellular stores and is mediated by activation of the α1A adrenergic receptor subtype. The α1A subtype is also required for the sustained elevation in [Ca2+]i induced by ATP+PE. In contrast, although synergistic stimulation of VP/OT release was eliminated by removal of PE and was blunted by benoxathian, an α1-R antagonist that is not subtype selective, no single α1-R subtype selective antagonist prevented sustained stimulation of VP/OT release by ATP+PE. Thus, sustained activation of α1-R is essential for the synergistic VP and OT response to ATP+PE, but multiple α1-R subtypes can support the response. Redundancy amongst the α1-R subunits in supporting this response is consistent with the predicted importance of the response for sustaining the elevated VP release required to prevent cardiovascular collapse during hemorrhage and sepsis.

Download Full-text

Sustained stimulation of vasopressin and oxytocin release by ATP and phenylephrine requires recruitment of desensitization-resistant P2X purinergic receptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00358.2009 ◽

2009 ◽

Vol 297 (4) ◽

pp. R940-R949 ◽

Cited By ~ 18

Author(s):

Dayane A. Gomes ◽

Zhilin Song ◽

Wanida Stevens ◽

Celia D. Sladek

Keyword(s):

Adrenergic Receptor ◽

Purinergic Receptors ◽

Purinergic Receptor ◽

Receptor Subtypes ◽

Hormone Response ◽

Oxytocin Release ◽

Initial Activation ◽

New Evidence ◽

Stimulation Of ◽

Sustained Activation

Coexposure of hypothalamo-neurohypophyseal system explants to ATP and phenylephrine [PE; an α1-adrenergic receptor (α1-AR) agonist] induces an extended elevation in vasopressin and oxytocin (VP/OT) release. New evidence is presented that this extended response is mediated by recruitment of desensitization-resistant ionotropic purinergic receptor subtypes (P2X-Rs): 1) Antagonists of the P2X2/3 and P2X7-Rs truncated the sustained VP/OT release induced by ATP+PE but did not alter the transient response to ATP alone. 2) The P2X2/3 and P2X7-R antagonists did not alter either ATP or ATP+PE-induced increases in [Ca2+]i. 3) P2X2/3 and P2X7-R agonists failed to elevate [Ca2+]i, while ATP-γ-S, an agonist for P2X2-Rs increased [Ca2+]iand induced a transient increase in VP/OT release. 4) A P2Y1-R antagonist did not prevent initiation of the synergistic, sustained stimulation of VP/OT release by ATP+PE but did reduce its duration. Thus, the desensitization-resistant P2X2/3 and P2X7-R subtypes are required for the sustained, synergistic hormone response to ATP+PE, while P2X2-Rs are responsible for the initial activation of Ca2+-influx by ATP and ATP stimulation of VP/OT release. Immunohistochemistry, coimmunoprecipitation, and Western blot analysis confirmed the presence of P2X2 and P2X3, P2X2/3, and P2X7-R protein, respectively in SON. These findings support the hypothesis that concurrent activation of P2X2-R and α1-AR induces calcium-driven recruitment of P2X2/3 and 7-Rs, allowing sustained activation of a homeostatic circuit. Recruitment of these receptors may provide sustained release of VP during dehydration and may be important for preventing hemorrhagic and septic shock.

Download Full-text

Noradrenergic control of central oxytocin release during lactation in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.3.e453 ◽

1998 ◽

Vol 274 (3) ◽

pp. E453-E458 ◽

Cited By ~ 9

Author(s):

Steven L. Bealer ◽

William R. Crowley

Keyword(s):

Cerebrospinal Fluid ◽

Adrenergic Receptors ◽

Adrenergic Receptor ◽

Additional Experiment ◽

Adrenergic Agonist ◽

Magnocellular Nuclei ◽

Artificial Cerebrospinal Fluid ◽

Oxytocin Release ◽

Stimulation Of

Noradrenergic systems regulate the systemic release of oxytocin (OT) in lactating rats. However, a role for norepinephrine (NE) in release of OT within the magnocellular nuclei during suckling has not been established. These studies were designed to determine 1) if suckling induces NE release in the supraoptic (SON) and paraventricular (PVN) nuclei of conscious rats and 2) the role of NE in the central, intranuclear release of OT within these nuclei. Female Holtzman rats were implanted with microdialysis probes adjacent to the PVN or SON on lactation days 8- 12. The following day, the pups were isolated from the dams for 4 h. Microdialysis probes were perfused with artificial cerebrospinal fluid (ACSF) or with ACSF containing an α- or a β-adrenergic receptor antagonist. Dialysate was collected before, during, and after suckling and analyzed for NE or OT. In an additional experiment, an α- or β-adrenergic agonist was administered via the microdialysis probes into the PVN in nonsuckled, lactating rats. Extracellular NE increased in the PVN during suckling but was not detectable in the SON. OT concentrations in dialysates from the PVN and SON significantly increased during suckling. Blockade of either α- (in both PVN and SON) or β- (PVN) adrenergic receptors prevented the suckling-induced increase in central OT release. OT release was increased in nonsuckled, lactating rats by central application of either an α- or β-adrenergic agonist. These data demonstrate that intranuclear NE release is increased in the PVN by suckling and that subsequent stimulation of both α- and β-noradrenergic receptors mediates intranuclear OT release.

Download Full-text

Differentiating the role of γ-aminobutyric acid type A (GABAA) receptor subtypes

Biochemical Society Transactions ◽

10.1042/bst0320553 ◽

2004 ◽

Vol 32 (3) ◽

pp. 553-556 ◽

Cited By ~ 38

Author(s):

K.A. Wafford ◽

A.J. Macaulay ◽

R. Fradley ◽

G.F. O'Meara ◽

D.S. Reynolds ◽

...

Keyword(s):

Gabaa Receptor ◽

Type A ◽

Aminobutyric Acid ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Acid Type ◽

Gabaa Receptor Subtypes ◽

Subtype Selective

The inhibitory tone maintained throughout the central nervous system relies predominantly on the activity of neuronal GABAA (γ-aminobutyric acid type A) receptors. This receptor family comprises various subtypes that have unique regional distributions, but little is known about the role played by each subtype. The majority of the receptors contain a γ2 subunit and are sensitive to modulation by BZs (benzodiazepines), but differ with regard to α and β subunits. Mutagenesis studies combined with molecular modelling have enabled a greater understanding of receptor structure and dynamics. This can now be extended to in vivo activity through translation to genetically modified mice containing these mutations. Ideally, the mutation should leave normal receptor function intact, and this is the case with mutations affecting the BZ-binding site of the GABAA receptor. We have generated mutations, which affect the BZ site of different α subunits, to enable discrimination of the various behavioural consequences of BZ drug action. This has aided our understanding of the roles played by individual GABAA receptor subtypes in particular behaviours. We have also used this technique to explore the role of different β subunits in conferring the anaesthetic activity of etomidate. This technique together with the development of subtype-selective compounds facilitates our understanding of the roles played by each receptor subtype.

Download Full-text

Role of non-NMDA receptors in vasopressin and oxytocin release from rat hypothalamo-neurohypophysial explants

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.280.2.r313 ◽

2001 ◽

Vol 280 (2) ◽

pp. R313-R322 ◽

Cited By ~ 19

Author(s):

Delmore J. Morsette ◽

Hanna Sidorowicz ◽

Celia D. Sladek

Keyword(s):

Nmda Receptors ◽

Kainic Acid ◽

Glutamate Receptor ◽

Supraoptic Nucleus ◽

Receptor Subtypes ◽

Hormone Release ◽

Oxytocin Release ◽

Nmda Glutamate Receptor ◽

Excitatory Transmitter

Glutamate is recognized as a prominent excitatory transmitter in the supraoptic nucleus (SON) and is involved in transmission of osmoregulatory information from the osmoreceptors to the vasopressin (VP) and oxytocin (OT) neurons. Explants of the hypothalamo-neurohypophysial system were utilized to characterize the roles of the non- N-methyl-d-aspartate (NMDA) glutamate receptor subtypes (non-NMDA-Rs), kainic acid receptors (KA-Rs), and aminopropionic acid receptors (AMPA-Rs) and to evaluate the interdependence of NMDA-Rs and non-NMDA-Rs in eliciting hormone release. Although both KA and AMPA increased hormone release, a specific agonist of the KA-Rs, SYM-2081, was not effective. This combined with the finding that cyclothiazide, an agent that inhibits the desensitization of AMPA-Rs, increased the VP response to both KA and AMPA indicates that the increase in hormone release induced by the non-NMDA agonists is mediated via AMPA-Rs, rather than KA-Rs. Inhibition of osmotically stimulated VP and OT release by a specific AMPA-R antagonist indicated that AMPA-Rs are essential for mediating osmotically stimulated hormone release. NMDA-stimulated VP but not OT release was prevented by blockade of non-NMDA-Rs, but AMPA-stimulated VP/OT release was not prevented by NMDA-R blockade.

Download Full-text

Physiological significance of α2-adrenergic receptor subtype diversity: one receptor is not enough

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00123.2002 ◽

2002 ◽

Vol 283 (2) ◽

pp. R287-R295 ◽

Cited By ~ 173

Author(s):

Melanie Philipp ◽

Marc Brede ◽

Lutz Hein

Keyword(s):

Blood Pressure ◽

Adrenergic Receptors ◽

Adrenergic Receptor ◽

Biological Effects ◽

Physiological Significance ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Biological Functions ◽

Novel Therapeutic Strategies ◽

Subtype Selective

α2-Adrenergic receptors mediate part of the diverse biological effects of the endogenous catecholamines epinephrine and norepinephrine. Three distinct subtypes of α2-adrenergic receptors, α2A, α2B, α2C, have been identified from multiple species. Because of the lack of sufficiently subtype-selective ligands, the specific biological functions of these receptor subtypes were largely unknown until recently. Gene-targeted mice carrying deletions in the genes encoding for individual α2-receptor subtypes have added important new insight into the physiological significance of adrenergic receptor diversity. Two different strategies have emerged to regulate adrenergic signal transduction. Some biological functions are controlled by two counteracting α2-receptor subtypes, e.g., α2A-receptors decrease sympathetic outflow and blood pressure, whereas the α2B-subtype increases blood pressure. Other biological functions are regulated by synergistic α2-receptor subtypes. The inhibitory presynaptic feedback loop that tightly regulates neurotransmitter release from adrenergic nerves also requires two receptor subtypes, α2A and α2C. Similarly, nociception is controlled at several levels by one of the three α2-receptor subtypes. Further investigation of the specific function of α2-subtypes will greatly enhance our understanding of the relevance of closely related receptor proteins and point out novel therapeutic strategies for subtype-selective drug development.

Download Full-text

Role of beta-adrenergic receptor subtypes in pig uterus contractility with inflammation

Scientific Reports ◽

10.1038/s41598-021-91184-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Barbara Jana ◽

Jarosław Całka

Keyword(s):

Adrenergic Receptors ◽

Adrenergic Receptor ◽

Domestic Animals ◽

Inhibitory Effect ◽

Receptor Subtypes ◽

Beta Adrenergic Receptor ◽

Pharmacological Modulation ◽

Uterine Inflammation ◽

Myometrial Contractility

AbstractUterine inflammation is a very common and serious condition in domestic animals. To development and progression of this pathology often lead disturbances in myometrial contractility. Participation of β1-, β2- and β3-adrenergic receptors (ARs) in noradrenaline (NA)-influenced contractility of the pig inflamed uterus was studied. The gilts of SAL- and E.coli-treated groups were administered saline or E.coli suspension into the uterine horns, respectively. Laparotomy was only done in the CON group. Compared to the period before NA administration, this neurotransmitter reduced the tension, amplitude and frequency in uterine strips of the CON and SAL groups. In the E.coli group, NA decreased the amplitude and frequency, and these parameters were lower than in other groups. In the CON, SAL and E.coli groups, β1- and β3-ARs antagonists in more cases did not significantly change and partly eliminated NA inhibitory effect on amplitude and frequency, as compared to NA action alone. In turn, β2-ARs antagonist completely abolished NA relaxatory effect on these parameters in three groups. Summarizing, NA decreases the contractile amplitude and frequency of pig inflamed uterus via all β-ARs subtypes, however, β2-ARs have the greatest importance. Given this, pharmacological modulation of particular β-ARs subtypes can be used to increase inflamed uterus contractility.

Download Full-text

Differential role of α 1 ‐adrenergic receptor subtypes in Ca 2+ ‐dependent and Ca 2+ ‐independent contraction in developing cerebral arteries

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.613.23 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Ashwani Mittal ◽

Ravi Goyal ◽

Nia Wedhas ◽

Lijun Shi ◽

Lawrence D. Longo

Keyword(s):

Adrenergic Receptor ◽

Cerebral Arteries ◽

Receptor Subtypes

Download Full-text

Social Isolation: How Can the Effects on the Cholinergic System Be Isolated?

Frontiers in Pharmacology ◽

10.3389/fphar.2021.716460 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jaromir Myslivecek

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Social Isolation ◽

Cholinergic System ◽

System Response ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Cholinergic Signaling ◽

The Central Nervous System

Social species form organizations that support individuals because the consequent social behaviors help these organisms survive. The isolation of these individuals may be a stressor. We reviewed the potential mechanisms of the effects of social isolation on cholinergic signaling and vice versa how changes in cholinergic signaling affect changes due to social isolation.There are two important problems regarding this topic. First, isolation schemes differ in their duration (1–165 days) and initiation (immediately after birth to adulthood). Second, there is an important problem that is generally not considered when studying the role of the cholinergic system in neurobehavioral correlates: muscarinic and nicotinic receptor subtypes do not differ sufficiently in their affinity for orthosteric site agonists and antagonists. Some potential cholinesterase inhibitors also affect other targets, such as receptors or other neurotransmitter systems. Therefore, the role of the cholinergic system in social isolation should be carefully considered, and multiple receptor systems may be involved in the central nervous system response, although some subtypes are involved in specific functions. To determine the role of a specific receptor subtype, the presence of a specific subtype in the central nervous system should be determined using search in knockout studies with the careful application of specific agonists/antagonists.

Download Full-text