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PubMed2001

Transgenic mouse models of angiotensin receptor subtype function in the cardiovascular system.

Angiotensin II mediates is biological actions via different subtypes of G protein-coupled receptors, termed AT(1) and AT(2) receptors. In rodents, two AT(1) receptors have been identified, AT(1A) and AT(1B), whereas in humans a single AT(1) receptor exists. Recently, a number of transgenic animal models have been generated which overexpress or lack functional angiotensin II receptor subtypes. This review focuses on the physiological significance of angiotensin II receptor subtype diversity in the cardiovascular system. In the mouse, AT(1A) receptors are the major regulators of cardiovascular homeostasis by determining vascular tone and natriuresis. In addition, AT(1A) receptors mediate growth-stimulating signals in vascular and cardiac myocytes. AT(1B) receptors participate in blood pressure regulation, and their functions become apparent when the AT(1A) receptor gene is deleted. Deletion of the mouse gene for the AT(2) receptor subtype led to hypersensitivity to pressor and antinatriuretic effects of angiotensin II in vivo, suggesting that the AT(2) receptor subtype counteracts some of the biological effects of AT(1) receptor signalling.

Angiotensin II↗
PubMed1998

NPY receptor subtypes involved in the contraction of the proximal colon of the rat.

Experiments were designed to determine the receptor subtype(s) involved in the contraction of the rat proximal colon to NPY. In this tissue, mRNA of Y2 and Y4 NPY receptor subtypes were highly expressed, whereas Y5 mRNA levels were very low and Y1 mRNA levels were intermediate. NPY analogues induced contractions with the following order of potency: rPP > hPP = PYY = NPY = [Leu31,Pro34]NPY > NPY(2-36) = [D-Trp32]NPY > NPY(33-36). Responses to NPY, PYY and NPY(13-36) were not or partially affected by tetrodotoxin, in contrast to the responses to [Leu31,Pro34]NPY, rPP, hPP and [D-Trp32]NPY which were fully blocked. Atropine did not inhibit the contractions to NPY, PYY and [Leu31,Pro34]NPY but significantly affected those to NPY(13-36), [D-Trp32]NPY, rPP and hPP. The specific Y1 receptor antagonist BIBP 3226 was ineffective but JCF 104 and JCF 105 (two compounds with preferential affinity toward the hY5 receptor versus the hY1 or hY2 receptor) abolished the contractions provoked by the NPY analogues. These results suggest that NPY activates three receptor subtypes, a Y2 subtype possibly by a direct action on the smooth muscle cells, as well as a Y4 and a Y5 (or 'Y5-like') subtype which, respectively, release acetylcholine and an unknown neurotransmitter.

Animals↗
PubMed2001

Expression pattern of human P2Y receptor subtypes: a quantitative reverse transcription-polymerase chain reaction study.

The diverse biological actions of extracellular nucleotides in tissues and cells are mediated by two distinct classes of P2 receptor, P2X and P2Y. The G protein-coupled P2Y receptors comprise at least six mammalian subtypes (P2Y(1,2,4,6,11,12)), all of which have been cloned from human tissues, as well as other species. The P2Y receptor subtypes differ in their pharmacological selectivity for various adenosine and uridine nucleotides, which overlap in some cases. Data concerning the mRNA expression patterns of five P2Y receptors (P2Y(1,2,4,6,11)) in different human tissues and cells are currently quite limited, while P2Y mRNA distribution in the human brain has not previously been studied. In this study, we have addressed this deficiency in receptor expression data by using a quantitative reverse transcription-polymerase chain reaction approach to measure the precise mRNA expression pattern of each P2Y receptor subtype in a number of human peripheral tissues and brain regions, from multiple individuals, as well as numerous human cell lines and primary cells. All five P2Y receptors exhibited widespread yet subtype-selective mRNA expression profiles throughout the human tissues, brain regions and cells used. Our extensive expression data indicate the many potentially important roles of P2Y receptors throughout the human body, and will help in elucidating the physiological function of each receptor subtype in a wide variety of human systems.

Actins↗
PubMed2001

Topographic distribution and developmental timecourse of auditory event-related potentials in two subtypes of attention-deficit hyperactivity disorder.

The effect of age on the topographic distribution of auditory event-related potentials (ERPs) recorded during a two-tone discrimination, or oddball, task was examined in two subtypes of attention deficit/hyperactivity disorder (AD/HD) as defined by the most recent diagnostic manual, DSM-IV. EEG was recorded at 17 sites from AD/HD predominantly inattentive type (n=50) and AD/HD combined type (n=50) subjects aged from 8 to 17 years 11 months. ERP components were quantified at each site. Results revealed topographic differences from controls (n=50) that were common to both subtypes (e.g. target and standard P2 amplitude, and standard P2 latency) or unique to a particular subtype of AD/HD (Inattentive type: target N1, N2, P3b and standard N2 amplitude, target P2 latency; Combined type: target N1, P2, N2 and P3b amplitude, target N2 and standard N1 latency). These group differences showed different age effects. The across-region results revealed differing patterns of abnormal component development for each subtype, indicating a qualitative difference in information processing stage deficits in each of these AD/HD subtypes.

Acoustic Stimulation↗
PubMed1999

Distribution of AP-2 subtypes in the adult mouse brain.

In the mammalian central nervous system (CNS), transcription factor activator protein 2 (AP-2) is one of the critical regulatory factors for neural gene expression and neural development. As AP-2 has diverged into several subtypes, i.e. AP-2alpha, -2beta, and 2.2, we investigated the distribution of the AP-2 subtypes in the adult mouse brain by in situ hybridization using subtype-specific probes. Though AP-2 was essentially expressed in most regions of the brain, the hippocampus and cerebellum Purkinje cells exhibited a relatively high concentration of transcripts of any of the AP-2 subtypes. Among AP-2alpha variants, the expression of variant 1 was considerably lower than that of variant 3. Hence, the expression pattern of AP-2alpha variant 3 is suggested to represent the major gene expression of AP-2alpha. On the other hand, the expression of AP-2beta messenger RNA (mRNA) was higher than that of AP-2alpha in many regions. Especially, the olfactory bulb, hippocampus, cerebellum, and cerebral cortex contained an abundance of these mRNAs. Different from those of AP-2alpha, AP-2beta mRNAs were detected in considerable amounts in the glanular cells as well as in Purkinje cells. AP-2.2 gene expression was weak throughout the brain. Consequently, we found that various AP-2 subtypes and variants were expressed in a similar distribution pattern with each having its own specific intensity but that their precise distribution profiles were not exactly the same. In the mature brain, AP-2 is thought to regulate neural gene expression through specific and redundant association with a target gene.

Animals↗
PubMedDate not supplied

Interaction of the nicotinic agonist (R,S)-3-pyridyl-1-methyl-2-(3-pyridyl)-azetidine (MPA) with nicotinic acetylcholine receptor subtypes expressed in cell lines and rat cortex.

The interaction of the nicotinic agonist (R,S)-3-pyridyl-1-methyl-2-(3-pyridyl)-azetidine (MPA) with different nicotinic acetylcholine receptor (nAChR) subtypes was studied in cell lines and rat cortex. MPA showed an affinity (Ki = 1.21 nM) which was higher than anatoxin-a > (-)-nicotine > (+)-[R]nornicotine > (-)-[S]nornicotine > and (+)-nicotine, but lower than cytisine (Ki = 0.46 nM) in competing for (-)-[3H]nicotine binding in M10 cells, which stably express the recombinant alpha4beta2 nAChR subtype. A one-binding site model was observed in all competing experiments between (-)-[3H]nicotine binding and each of the agonists studied in M10 cells. MPA showed a 13-fold higher affinity for (-)-[3H]nicotine binding sites compared to the [3H]epibatidine binding sites in rat cortical membranes. In human neuroblastoma SH-SY5Y cells, which predominantly express the alpha3 nAChR subunit mRNA, MPA displaced [3H]epibatidine binding from a single population of the binding sites with an affinity in the same nM range as that observed MPA in displacing [3H]epibatidine binding in rat cortical membranes. Chronic treatment of M10 cells with MPA significantly up-regulated the number of (-)-[3H]nicotine binding sites in a concentration dependent manner. Thus MPA appears to have higher affinity to alpha4-subunit containing receptor subtype than alpha3-subunit containing receptor subtype of nAChRs. Furthermore MPA binds to alpha4beta2 receptor subtype with higher affinity than (-)-nicotine and behaves, opposite to cytisine, as a fult agonist in up-regulating the number of nAChRs.

Alkaloids↗
PubMed1998

The family of sodium-dependent glutamate transporters: a focus on the GLT-1/EAAT2 subtype.

The acidic amino acids, glutamate and aspartate, are the predominant excitatory neurotransmitters in the mammalian CNS. Under many pathologic conditions, these excitatory amino acids (EAAs) accumulate in the extracellular fluid in CNS and the resultant excessive activation of EAA receptors contributes to brain injury through a process known as 'excitotoxicity'. Unlike many other neurotransmitters, there is no evidence for extracellular metabolism of EAAs, rather, they are cleared by Na+-dependent transport mechanisms. Therefore, this transport process is important for ensuring crisp synaptic signaling as well as limiting the excitotoxic potential of EAAs. With the cloning of five distinct EAA transporters, a variety of tools were developed to characterize individual transporter subtypes, including specific antibodies, expression systems, and probes to delete/knock-down expression of each subtype. These tools are beginning to provide fundamental information that has the potential to impact our understanding of EAA physiology and pathophysiology. For example, biophysical studies of the cloned transporters have led to the observation that some subtypes function as ligand-gated ion channels as well as transporters. With these reagents, it has also been possible to explore the relative contributions of each transporter to the clearance of extracellular EAAs and to begin to examine the regulation of specific transporter subtypes. In this review, an overview of the properties of the transporter subtypes will be presented. The evidence which suggests that the transporter, GLT1/EAAT2, may be sufficient to explain a large percentage of forebrain transport will be critically reviewed. Finally, the studies of regulation of GLT-1 in vitro and in vivo will be described.

ATP-Binding Cassette Transporters↗
PubMed2003

HLA-B27 subtypes determination in patients with ankylosing spondylitis from Zulia, Venezuela.

To perform an investigation regarding the distribution of the human leukocyte antigen (HLA)-B27 subtypes in the Zulian population with ankylosing spondylitis (AS), 48 unrelated Mestizos, HLA-B27 positive by serology, were studied using the polymerase chain reaction-specific sequence oligonucleotides probe (PCR-SSOP) and specific sequence primers (SSP) to analyze the polymorphism in exons 2 and 3 of the HLA-B27 gene. Only two of eight HLA-B27 subtypes studied (B*2701-B*2708) were found. The distribution of these alleles in the population of patients was: B*2705, 68.8%, and B*2702, 31.2%. B*2705 subtype showed significant association with patients being male. In the healthy controls, the most common subtype was B*2708. These results were compared with frequencies reported in other Mestizo and Spanish populations and showed significant differences, such as a high frequency of B*2702. Such results show that HLA*B2705 and HLA*B2702 are the subtypes most frequently associated with AS in our Mestizo population and suggest a possible protector role for HLA*B2708, which was found only in the healthy population.

Adolescent↗
PubMed1997

The three subtypes of atrial natriuretic peptide (ANP) receptors are expressed in the rat adrenal gland.

Atrial natriuretic peptide (ANP) actions are mediated by highly selective and specific receptors. Three subtypes have been characterized and cloned: ANP receptor-A (or GC-A), -B (or GC-B) and -C (the so-called clearance receptor). In rat adrenal gland, the mRNA for each subtype was detected using 35S-dUTP or digoxigenin-11-dUTP specific labeled probes, and in situ hybridization at light and electron microscopic levels respectively. The three subtypes were expressed the most abundantly in the zona glomerulosa. The amount of GC-A mRNA expression, quantified using macro-autoradiography and densitometry, was higher than the amounts of GC-B mRNA and ANPR-C mRNA both in zona glomerulosa and medullary of adrenal gland. At electron microscopic level, the three subtypes of ANPR were revealed in glomerulosa cells. A noticeable signal was also present in the medullary area, especially for GC-A mRNA, in adrenaline-containing chromaffin cells. No signal was detected in noradrenaline-containing chromaffin cells. The subcellular localization of the three mRNAs is similar: in the cytoplasmic matrix and in the euchromatin of the nucleus in each cell of glomerulosa, and in the same compartments of the adrenaline-containing chromaffin cells. These data indicate that the adrenal gland is an important target tissue for ANP action both in glomerulosa cells and adrenaline-containing chromaffin cells. The mRNA expression levels were different for each ANPR subtype.

Adrenal Medulla↗
PubMedDate not supplied

Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors.

There are five subtypes of muscarinic acetylcholine receptors (M(1) to M(5)) which control a large number of physiological processes, such as the function of heart and smooth muscles, glandular secretion, release of neurotransmitters, gene expression and cognitive functions as learning and memory. A selective ligand is very useful for studying the function of a subtype in presence of other subtypes, which is the most common situation, since a cell or an organ usually has several subtypes. There are many non-selective muscarinic ligands, but only few selective ones. Mambas, African snakes of genus Dendroaspis have toxins, muscarinic toxins, that are selective for M(1), M(2) and M(4) receptors. They consist of 63-66 amino acids and four disulfides which form four loops. They are members of a large group of snake toxins, three-finger toxins; three loops are extended like the middle fingers of a hand and the disulfides and the shortest loop are in the palm of the hand. Some of the toxins target the allosteric site which is located in a cleft of the receptor molecule close to its extracellular part. A possible explanation to the good selectivity is that the toxins bind to the allosteric site, but because of their size they probably also bind to extracellular parts of the receptors which are rather different in the various subtypes. Some other allosteric ligands also have good selectivity, the alkaloid brucine and derivatives are selective for M(1), M(3) and M(4) receptors. Muscarinic toxins have been used in several types of experiments. For instance radioactively labeled M(1) and M(4) selective toxins were used in autoradiography of hippocampus from Alzheimer patients. One significant change in the receptor content was detected in one region of the hippocampus, dentate gyrus, where M(4) receptors were reduced by 50% in patients as compared to age-matched controls. Hippocampus is essential for memory consolidation. M(4) receptors in dentate gyrus may play a role, since they decreased in Alzheimers disease which destroys the memory. Another indication of the role of M(4) receptors for memory is that injection of the M(4) selective antagonist muscarinic toxin 3 (M(4)-toxin 1) into rat hippocampus produced amnesia.

Amino Acid Sequence↗
PubMed2002

Role of adrenoceptor subtypes in memory consolidation.

Noradrenaline release in areas within the forebrain occurs following activation of noradrenergic cells in the locus coeruleus (LoC). Release of noradrenaline by attentional/arousal/vigilance factors appears to be essential for learning and is responsible for the consolidation of memory. Noradrenaline can activate any of nine different adrenoceptor (AR) subtypes in the brain and selectivity of action may be achieved by the spatial location and relative density of the AR subtypes, by different affinities of the different subtypes and by temporal selectivity in terms of when the different ARs are activated in the memory formation process. This review examines the use of selective agonists and antagonists to determine the roles of the AR subtypes in the one-trial discriminated avoidance learning paradigm in the chick. A model is developed that integrates noradrenergic activity in basal ganglia (lobus parolfactorius (LPO)) and association cortex (intermediate medial hyperstriatum ventrale (IMHV)) leading to the consolidation of memory 30 min after training. There is evidence that beta(2)- and beta(3)-ARs are important in the association area but require input from alpha(2)-AR stimulated activity in the basal ganglia for consolidation. On the other hand, alpha(1)-AR activation in the IMHV is inhibitory and prevents consolidation. While there is no role for beta(1)-ARs in memory consolidation, they play a role in short-term memory (STM). The use of the precocial chick has clear advantages in having a temporally discrete learning task which allows for discrimination memory and whose development can be followed at discrete intervals after learning. These studies reveal clear roles for AR subtypes in the formation and consolidation of memory in the chick, which have allowed the development of a model that can now be tested in mammalian systems.

Animals↗
PubMed2001

Changes of the expression of 5-HT receptor subtype mRNAs in rat dorsal root ganglion by complete Freund's adjuvant-induced inflammation.

By using the reverse transcriptase polymerase chain reaction technique, the expression of 5-hydroxytryptamine (5-HT) receptor subtype mRNAs in the rat lumbar dorsal root ganglion (DRG) was investigated following unilateral injection of complete Freund's adjuvant (CFA) into the rat hind paw. The results showed that 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(1F), 5-HT(2A), 5-HT(3), 5-HT(4), 5-HT(5A) and 5-HT(7) receptor subtypes were present in the rat lumbar DRG. CFA injection resulted in a significant increase in mRNA level of 5-HT(1A), 5-HT(1B), 5-HT(1F), 5-HT(2A), 5-HT(3), 5-HT(4) and 5-HT(7) receptor subtypes and a marked induction of 5-HT(2C) subtype mRNA in the DRG. The present results suggest the important roles for these 5-HT receptor subtypes in generating peripheral nociceptive signaling and provide evidence to elucidate the mechanism of 5-HT in nociception.

Actins↗
PubMed2002

Complex regional pain syndrome: are there distinct subtypes and sequential stages of the syndrome?

This study tested for evidence supporting the clinical lore of three sequential stages of complex regional pain syndrome (CRPS) and examined the characteristics of possible CRPS subtypes. A series of 113 patients meeting IASP criteria for CRPS underwent standardized history and physical examinations to assess CRPS signs and symptoms in four domains identified in previous research: pain/sensory abnormalities, vasomotor dysfunction, edema/sudomotor dysfunction, and motor/trophic changes. K-Means cluster analysis was used to derive three relatively homogeneous CRPS patient subgroups based on similarity of sign/symptom patterns in these domains. The resulting CRPS subgroups did not differ significantly regarding pain duration as might be expected in a sequential staging model. However, the derived subgroups were statistically-distinct, and suggested three possible CRPS subtypes: (1) a relatively limited syndrome with vasomotor signs predominating, (2) a relatively limited syndrome with neuropathic pain/sensory abnormalities predominating, and (3) a florid CRPS syndrome similar to "classic RSD" descriptions. Subtype 3 showed the highest levels of motor/trophic signs and possible disuse-related changes (osteopenia) on bone scan, despite having directionally the briefest pain duration of the three groups. EMG/NCV testing suggests that Subtype 2 may reflect CRPS-Type 2 (causalgia). Overall, these results are consistent with limited previous work that argues against three sequential stages of CRPS. However, several distinct CRPS subtypes are suggested, and these could ultimately have utility in targeting treatment more effectively.

Adult↗
PubMed1998

Tamsulosin: assessment of affinity of 3H-prazosin bindings to two alpha1-adrenoceptor subtypes (alpha1H and alpha1L) in bovine prostate and rat heart and brain.

1. The present study was designed to assess the displacement potencies of tamsulosin to 3H-prazosin bindings in two alpha1-adrenoceptor (AR) subtypes (alpha1H and alpha1L) in bovine prostate, rat heart and brain compared with those of amosulalol, labetalol, ketanserin, clonidine and propranolol. 2. The pKi values of tamsulosin to alpha1H and alpha1L subtypes in bovine prostate were 9.13 and 8.99 and these values were almost the same as those of prazosin. On the other hand, low pKi binding values of amosulalol, labetalol, ketanserin, clonidine and propranolol to these subtypes were observed. 3. Low pKi values of tamsulosin to alpha2- and beta-ARs and muscarinic and 5HT2 receptors in the rat brain were observed. 4. These results suggest that tamsulosin has high affinities to alpha1L-AR subtypes in bovine prostate and rat hearts as well as alpha1H-AR subtypes, implying an inhibitory effect of this drug on the contraction of the prostate.

Adrenergic alpha-Antagonists↗
PubMed1997

[3H]1,3-di(2-tolyl)guanidine and [3H](+)pentazocine binding sites in the rat brain: autoradiographic visualization of the putative sigma1 and sigma2 receptor subtypes.

Sigma (sigma) receptors have generated a great deal of interest on the basis of their possible role in psychosis and on locomotor behaviors. The effects of sigma drugs on these various functions are apparently mediated by different sigma receptor subtypes (sigma1 and sigma2). However, little information is currently available on the discrete anatomical distribution of these putative sigma receptor subtypes in the rat brain. The aim of the present study was to investigate, by quantitative autoradiography, the respective distribution of purported sigma1 and sigma2 receptor subtypes in the rat brain using [3H]1,3-di(2-tolyl)guanidine, a universal sigma ligand, and [3H](+)pentazocine, a selective sigma1 ligand. Putative sigma2 receptor sites were visualized using [3H]1,3-di(2-tolyl)guanidine in presence of a saturating concentration of (+)pentazocine. Specific [3H]1,3-di(tolyl)guanidine and [3H](+)pentazocine binding sites were found to be widely but discretely distributed in the rat brain. The highest densities of specific labeling were seen in various cranial nerve nuclei, followed by certain hippocampal sub-fields and laminae, the red nucleus, the interpeduncular nucleus and mid-layers of primary and secondary motor cortices. Lower amounts of specific binding were present in various other structures including most thalamic and hypothalamic nuclei, and the cerebellum. Interestingly, [3H]1,3-di(2-tolyl)guanidine binding in the motor cortex was found to be particularly resistant to a saturating concentration of (+)pentazocine suggesting an enrichment in the putative sigma2 receptor subtype. This also applies for a few other structures such as the nucleus accumbens, substantia nigra pars reticulata, central gray matter, occulomotor nucleus and cerebellum. On the other hand, the sigma1 subtype is more abundant in most other regions with the highest densities seen in the dentate gyrus of the hippocampal formation, facial nucleus, and various thalamic and hypothalamic nuclei. The comparative localization of the sigma1 and sigma2 receptor binding sites probably relates to the differential effects of sigma1 and sigma2 drugs in the rat brain.

Analgesics, Opioid↗
PubMed1997

Formalin-induced nociceptive behavior and edema: involvement of multiple peripheral 5-hydroxytryptamine receptor subtypes.

The role of 5-hydroxytryptamine and its receptor subtypes in the development of acute inflammation was investigated using the rat paw formalin test as a model for pain (measured by flinching behavior) and edema formation (measured by plethysmometry). The role of endogenously released 5-hydroxytryptamine was assessed using 5-hydroxytryptamine receptor subtype-selective antagonists co-injected with 2.5% formalin, while the receptor subtypes involved in the inflammatory process were further defined by co-injection of 5-hydroxytryptamine or 5-hydroxytryptamine receptor subtype-selective agonists with 0.5% formalin in anticipation of an augmented response. When co-administered with 2.5% formalin, propranolol, tropisetron or GR113808A, but not ketanserin, effectively blocked nociceptive behavior. In the presence of 0.5% formalin, 5-carboxamidotryptamine, 1-(m-chlorophenyl) biguanide or 5-methoxytryptamine, but not (+/-)-1-4-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane, augmented the flinching response. These data suggest involvement of 5-hydroxytryptamine1, 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors in peripheral nociception. There may be some dissociation of nociception and edema formation, since no single 5-hydroxytryptamine receptor antagonist inhibited edema formation with 2.5% formalin; however, with 0.5% formalin, edema formation was enhanced by co-administration of 5-hydroxytryptamine, 5-carboxamidotryptamine, (+/-)-1-4-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane or 5-methoxytryptamine, but not 1-(m-chlorophenyl) biguanide. These data suggest involvement of 5-hydroxytryptamine1, 5-hydroxytryptamine2 and possibly 5-hydroxytryptamine4 receptors in edema formation. These results confirm the involvement of 5-hydroxytryptamine1 and 5-hydroxytryptamine3 receptor subtypes in peripheral nociception associated with acute inflammation and further suggest an involvement of the more recently characterized 5-hydroxytryptamine4 receptor in this process. There appears to be a dissociation in 5-hydroxytryptamine receptors involved in peripheral nociception and edema formation.

Animals↗
PubMed1998

A non-pungent resiniferatoxin analogue, phorbol 12-phenylacetate 13 acetate 20-homovanillate, reveals vanilloid receptor subtypes on rat trigeminal ganglion neurons.

Capsaicin, the vanilloid responsible for the pungent taste of hot peppers, binds to receptors found primarily in polymodal nociceptors. Capsaicin initially stimulates polymodal nociceptors and subsequently inhibits them from responding to a variety of stimuli. This property makes it useful clinically as an analgesic and anti-inflammatory compound. There is mounting, albeit indirect, evidence for the existence of several subtypes of vanilloid receptors. One such piece of evidence comes from studying analogues of capsaicin, such as phorbol 12-phenylacetate 13 acetate 20-homovanillate. This compound binds to (capsaicin) vanilloid receptors on sensory neurons, but unlike capsaicin it is non-pungent and does not produce hypothermia. To determine how sensory neurons respond to phorbol 12-phenylacetate 13 acetate 20-homovanillate, and to compare these responses with those evoked by capsaicin, whole-cell patch-clamp measurements were performed on cultured rat trigeminal ganglion neurons. It was found that 63% of the neurons held at -60 mV were activated by 3 microM, phorbol 12-phenylacetate 13 acetate 20-homovanillate, and 87% of these were also activated by 1 microM capsaicin. In a given neuron, phorbol 12-phenylacetate 13 acetate 20-homovanillate, like capsaicin, could activate kinetically distinct inward currents. The current-voltage curves characterizing phorbol 12-phenylacetate 13 acetate 20-homovanillate responses were asymmetric and had reversal potentials at -5.8 +/- 6.0 mV and 10.4 +/- 4 mV. The averaged dose-response curves for phorbol 12-phenylacetate 13 acetate 20-homovanillate were fit to the Hill equation and had binding constants (K(1/2)s) of 2.73 microM and 0.96 microM and Hill coefficients (ns) of approximately 1 for a rapidly- and slowly-activating current, respectively. These parameters are consistent with those obtained from binding experiments and calcium-influx experiments on sensory nerves. Repeated applications of phorbol 12-phenylacetate 13 acetate 20-homovanillate every 3 min caused a complete reduction in the rapidly-activating currents leaving only a reduced slowly-activating current. This provides strong evidence for the independence of these currents and the existence of subtypes of vanilloid receptors. Additional evidence for the existence of receptor subtypes is that 10 microM capsazepine, a specific and competitive inhibitor of capsaicin-evoked responses, did not inhibit the phorbol 12-phenylacetate 13 acetate 20-homovanillate-induced currents in some neurons and partially inhibited them in other neurons. Thus, there are capsazepine-sensitive and capsazepine-insensitive subtypes of vanilloid receptors. In summary, we have obtained electrophysiological and pharmacological evidence for distinct subtypes of vanilloid receptors.

Animals↗
PubMed1998

D-amphetamine and L-5-hydroxytryptophan-induced behaviours in mice with genetically-altered expression of the alpha2C-adrenergic receptor subtype.

Three human and mouse genes encoding alpha2-adrenoceptor subtypes (alpha2A, alpha2B, and alpha2C) have been cloned. The alpha2C-adrenoceptor is the most abundant alpha2-adrenoceptor subtype in the striatum and modulates metabolism of both dopamine and serotonin. To investigate the possible involvement of the alpha2C-adrenoceptor subtype in behaviours regulated by dopamine and serotonin, two strains of genetically-engineered mice were examined. One had a targeted inactivation of the alpha2C-adrenoceptor gene, and the other had tissue-specific over-expression of alpha2C-adrenoceptors. The locomotor activity of the mice was evaluated after stimulation with D-amphetamine, and the behavioural serotonin syndrome and head twitches were investigated after L-5-hydroxytryptophan treatment. In addition, the effects of D-amphetamine and L-5-hydroxytryptophan were studied after pretreatment with dexmedetomidine, a subtype-nonselective alpha2-adrenoceptor agonist. The lack of alpha2C-adrenoceptor expression increased and the over-expression of alpha2C-adrenoceptors decreased the response to D-amphetamine stimulation. The effect of alpha2C-adrenoceptor gene inactivation was more prominent in D-amphetamine-treated males than in females. Dexmedetomidine inhibited D-amphetamine-induced hyperlocomotion and the L-5-hydroxytryptophan-induced serotonin syndrome, but the inhibition was attenuated in mice lacking alpha2C-adrenoceptors. However, the head twitches induced by L-5-hydroxytryptophan were effectively inhibited by dexmedetomidine in all studied mice, which suggests that alpha2A-adrenoceptors mediate the inhibition of the head twitch response. The results lend further support to the proposed existence of functionally distinct alpha2-adrenoceptor subtypes that can serve as new and specific therapeutic targets in various neuropsychiatric diseases.

5-Hydroxytryptophan↗