Localization of the kappa opioid receptor gene to human chromosome band 8q11.2.
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Animals↗
Biomedical subjects
G I Bell
Publications and source records attributed to G I Bell.
Human type I pituitary adenylate cyclase activating polypeptide receptor (ADCYAP1R): localization to chromosome band 7p14 and integration into the cytogenetic, physical, and genetic map of chromosome 7.
The gene encoding the human type I pituitary adenylate cyclase activating polypeptide receptor (ADCYAP1R1) was mapped to chromosome 7 by PCR analysis of genomic DNA from a human/rodent somatic cell hybrid mapping panel. This assignment was confirmed and the gene localized to chromosome band 7p14 by fluorescence in situ hybridization. A yeast artificial chromosome containing ADCYAP1R1 was identified in the CEPH "B" Mega-YAC library. This YAC includes two highly polymorphic dinucleotide repeat sequences that will facilitate genetic studies of the contribution of ADCYAP1R1 in disease states of the central nervous and neuroendocrine systems.
Animals↗
G protein-activated inwardly rectifying potassium channel (GIRK1/KGA) mRNA in adult rat heart and brain by in situ hybridization histochemistry.
GIRK1/KGA (referred to as GIRK1) is a member of the inwardly rectifying K+ channel family and is activated by G protein-linked receptors. The activation of this channel leads to hyperpolarization of the plasma membrane and is fundamental to the control of atrial and neuronal excitability. RNA blotting studies have shown that GIRK1 is expressed in the atrium of the heart and in the brain. We have used in situ hybridization histochemistry to characterize the pattern of expression of GIRK1 mRNA in adult rat heart and brain. In heart, expression of GIRK1 mRNA is homogeneous throughout the atria. There is no significant ventricular expression, although the conduction bundles were not specifically identified. GIRK1 mRNA expression in the brain is widespread with highest levels in the cortex, septum, hippocampus, thalamus, amygdala, cerebellum, and many nuclei of the midbrain and hindbrain, including red nucleus, inferior colliculus, pontine nucleus, nucleus of the solitary tract, and multiple cranial nerve nuclei (motor and sensory components). This detailed map of GIRK1 mRNA expression provides a basis for further study of this important new family of K+ channels.
Animals↗
Localization of somatostatin (SRIF) SSTR-1, SSTR-2 and SSTR-3 receptor mRNA in rat brain by in situ hybridization.
In situ hybridization histochemistry was performed to analyse the distribution of the messenger RNA (mRNA) of three putative somatostatin (SRIF) receptors in rat brain, using oligonucleotide probes derived from the cDNA coding for SSTR-1, SSTR-2, and SSTR-3 receptors. SSTR-1 signals were found in layers V-VI of the cerebral cortex, in primary olfactory cortex, taenia tecta, subiculum, entorhinal cortex, granular layer of the dentate gyrus, amygdala and cerebellar nuclei. Signals for SSTR-2 were found in the frontal cerebral cortex (layers IV, V and VI), taenia tecta, claustrum, endopiriform nucleus, locus coeruleus, medial habenula, subiculum, granular cell layer of the dentate gyrus and amygdala. High levels of SSTR-3 hybridization were found in the olfactory bulb, primary olfactory cortex, islands of Calleja, medial habenula, amygdala, granular layer of the dentate gyrus, various thalamic and pontine nuclei and in the granular and Purkinje cell layers of the cerebellum. The distribution of the hybridization signals of the oligoprobes is consistent with the labelling of specific SRIF binding sites in rat brain. Especially, SSTR-2 and SSTR-1 oligos seem to label regions in which SS-1 and SS-2 receptors, respectively, have been previously characterized in autoradiographical studies. The situation is less clear with SSTR-3 mRNA, since SRIF binding in adult rats is usually low or absent in cerebellum, although some cerebellar nuclei appear to be labelled in the adult. The localization of SSTR-1, SSTR-2 and SSTR-3 mRNAs suggests that SRIF receptor subtypes in rat brain show profound differences in their distribution and are involved in a variety of central, in addition to neuroendocrine, functions.
Animals↗
Maturity-onset diabetes of the young.
Maturity-onset diabetes of the young (MODY) is a subtype of noninsulin dependent diabetes mellitus (NIDDM). It is characterized by an early age of onset and autosomal dominant mode of inheritance. These features and the availability of large multigenerational pedigrees make MODY useful for genetic studies of diabetes. In the large, 5-generational RW pedigree, MODY is tightly linked to genetic markers on chromosome 20q. Affected subjects in this family show abnormalities of carbohydrate metabolism varying from impaired glucose tolerance (IGT) to severe diabetes. Approximately 30% of diabetic subjects become insulin requiring and vascular complications occur. MODY is also linked to the glucokinase gene on chromosome 7p and many different mutations associated with MODY have been identified in this gene. MODY due to mutations in the glucokinase gene is a relatively mild form of diabetes with mild fasting hyperglycemia and IGT in the majority. IT is rarely insulin requiring and rarely has vascular complications. Clinical studies indicate that the genetic or primary defect in MODY is characterized by deranged and deficient insulin secretion and not by insulin resistance and that there are quantitative and qualitative differences in insulin secretory defects which differentiate subjects with MODY due to glucokinase mutations from those with mutations in the gene on chromosome 20q. These differences correlate with the severity of diabetes between these two genetic forms of MODY.
Diabetes Mellitus, Type 2↗
Differential expression of messenger RNAs for somatostatin receptor subtypes SSTR1, SSTR2 and SSTR3 in adult rat brain: analysis by RNA blotting and in situ hybridization histochemistry.
The messenger RNAs encoding three somatostatin receptor subtypes, SSTR1, SSTR2 and SSTR3, were detected in rat by RNA blotting and in situ hybridization histochemistry to identify the sites of synthesis and expression of these somatostatin receptor subtypes. RNA blotting revealed that SSTR1 messenger RNA of 3.8 kilobases was highly expressed in cerebral cortex, hippocampus, midbrain and hypothalamus. In situ hybridization histochemistry revealed that SSTR1 messenger RNA was localized to discrete layers of the cerebral cortex, the piriform cortex and the dentate gyrus of the hippocampus. SSTR1 messenger RNA was expressed at low levels in the cerebellum and pituitary and was not detectable in striatum or other peripheral organs. At least two SSTR2 messenger RNAs were detected by RNA blotting of 2.4 and 2.8 kilobases which correspond to the size of the spliced and unspliced forms of this receptor messenger RNA. SSTR2 messenger RNA detected by in situ hybridization is diffusely expressed in cerebral cortex and amygdala but is discretely localized to dentate gyrus in the hippocampus, medial habenula and ventromedial and dorsomedial nuclei and arcuate nucleus of the hypothalamus. The levels of SSTR2 messenger RNA are very low in the cerebellum and were not observed in the striatum or peripheral tissues other than the pituitary or adrenal gland. A single SSTR3 messenger RNA of 4.0 kilobases was seen in hippocampus, cerebral cortex, midbrain, hypothalamus and pituitary. However, the tissue with the highest levels of SSTR3 messenger RNA is the cerebellum with messenger RNA localized to the granule cell layer. The expression of the three different somatostatin receptor messenger RNAs are distinct but overlapping. Such distinct expression may contribute to the selective biological roles of the receptor subtypes.
Animals↗
The cloned kappa opioid receptor couples to an N-type calcium current in undifferentiated PC-12 cells.
We have recently reported the cloning of a mouse kappa opioid receptor cDNA. Following transfection of the kappa receptor cDNA into COS-1 cells, a receptor is expressed with the pharmacological specificity of a kappa opioid receptor. To further analyse its functional properties, we have stably expressed the kappa opioid receptor in undifferentiated PC-12 cells, a pheochromocytoma clonal cell line, which do not endogenously express this receptor. We have previously shown that kappa opioid agonists selectively bind to these PC-12 membranes with high affinity. Here we show that kappa selective agonists are able to inhibit accumulation of cyclic adenosine monophosphate in a stereoselective manner. Further, the kappa agonist U-50,488 is able to inhibit an N-type calcium current in a pertussis toxin sensitive manner; this inhibition is blocked by the kappa-selective antagonist norbinaltorphimine. Inhibition of the calcium current via the kappa receptor is stereoselective as the agonist levorphanol is able to mediate inhibition whereas in the same cells dextrorphan is ineffective. This is the first demonstration that the cloned kappa opioid receptor functionally couples to a calcium current, as has been reported for kappa receptors expressed endogenously in the nervous system. Kappa opioid receptors are thought to be important in pain pathways, learning and memory deficits, and seizure activity. A major physiological action of the dynorphins, the endogenous ligands of the kappa receptor, is thought to be inhibition of neurotransmitter release at presynaptic terminals. N-type calcium channels may be important in neurotransmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Immunological detection of isoforms of the somatostatin receptor subtype, SSTR2.
Somatostatin (SRIF) induces its diverse physiological actions through interactions with different receptor subtypes. Multiple SRIF receptor subtypes have recently been cloned. To analyze the physical properties of receptor subtype SSTR2, two different peptide-directed antibodies were generated against SSTR2. Antibody "2e3," directed against the peptide SSCTINWPGESGAWYT (residues 191-206), corresponding to a region in the predicted third extracellular domain of mouse SSTR2, and antibody "2i4," directed against the peptide SGTEDGERSDS (residues 333-343) from the predicted cytoplasmic tail of mouse SSTR2, were developed. In Chinese hamster ovary (CHO) cells stably expressing the mouse SSTR2 gene (CHOB), the antibody 2e3 recognized specifically a protein of 93-kDa protein by immunoblotting. No specific immunoreactivity was detected by 2e3 in nontransfected CHO cells or CHO cells stably expressing vector alone or human SSTR1 or mouse SSTR3 genes. The antibody 2i4 specifically immunoprecipitated SSTR2 solubilized from CHOB cells that could be labeled with the SSTR2-specific ligand 125I-MK-678. Furthermore, both 2e3 and 2i4 specifically immunoprecipitated 93-kDa [35S]methionine-labeled proteins from CHOB cells, indicating that they recognize the same proteins. In contrast to studies in CHOB cells, immunoblotting studies showed that 2e3 detected specifically a single 148-kDa protein from different regions of the rat brain that have previously been shown to express high levels of SSTR2 mRNA and SRIF receptors with high affinity for 125I-MK-678. In contrast, no immunoreactivity was detected in rat kidney, liver, or lung, which do not express SSTR2. No 93-kDa protein was detected specifically in the rat brain.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Dinucleotide repeat polymorphism at D9S328E (EST hbc220).
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Alleles↗
Mutations in the glucokinase gene are not a major cause of late-onset type 2 (non-insulin-dependent) diabetes mellitus in Japanese subjects.
The role of the glucokinase gene in the development of diabetes in a group of 349 Japanese subjects with late-onset Type 2 diabetes was examined. These diabetic subjects and 197 non-diabetic controls were typed at two simple tandem repeat DNA polymorphisms in the glucokinase gene termed GCK2 and GCK3. Six and five alleles were evident in Japanese subjects at GCK2 and GCK3, respectively. There were no significant differences in allele, genotype or haplotype frequencies between diabetic and normal groups. In addition, the glucokinase gene of 340 diabetic and 170 non-diabetic Japanese subjects was screened for mutations using single strand conformation polymorphism analysis. Four nucleotide substitutions were identified: a silent substitution in exon 4 in the codon for proline 145 (CCC-->CCG), and A-->T, C-->G, and C-->A substitutions in introns 1b, 3, and 5, respectively. There were no significant differences in the frequencies of these nucleotide substitutions between diabetic and non-diabetic groups. These results suggest that glucokinase gene defects are not a major cause of late-onset Type 2 diabetes in Japanese subjects.
Amino Acid Sequence↗
Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations.
Pancreatic beta-cell function was studied in six subjects with mutations in the enzyme glucokinase (GCK) who were found to have elevated fasting and postprandial glucose levels in comparison to six normoglycemic controls. Insulin secretion rates (ISRs) were estimated by deconvolution of peripheral C-peptide values using a two-compartment model and individual C-peptide kinetics obtained after bolus intravenous injections of biosynthetic human C-peptide. First-phase insulin secretory responses to intravenous glucose and insulin secretion rates over a 24-h period on a weight maintenance diet were not different in subjects with GCK mutations and controls. However, the dose-response curve relating glucose and ISR obtained during graded intravenous glucose infusions was shifted to the right in the subjects with GCK mutations and average ISRs over a glucose range between 5 and 9 mM were 61% lower than those in controls. In the controls, the beta cell was most sensitive to an increase in glucose at concentrations between 5.5 and 6.0 mM, whereas in the patients with GCK mutations the point of maximal responsiveness was increased to between 6.5 and 7.5 mM. Even mutations that resulted in mild impairment of in vitro enzyme activity were associated with a > 50% reduction in ISR. The responsiveness of the beta cell to glucose was increased by 45% in the subjects with mutations after a 42-h intravenous glucose infusion at a rate of 4-6 mg/kg per min. During oscillatory glucose infusion with a period of 144 min, profiles from the subjects with mutations revealed reduced spectral power at 144 min for glucose and ISR compared with controls, indicating decreased ability to entrain the beta cell with exogenous glucose. In conclusion, subjects with mutations in GCK demonstrate decreased responsiveness of the beta cell to glucose manifest by a shift in the glucose ISR dose-response curve to the right and reduced ability to entrain the ultradian oscillations of insulin secretion with exogenous glucose. These results support a key role for the enzyme GCK in determining the in vivo glucose/ISR dose-response relationships and define the alterations in beta-cell responsiveness that occur in subjects with GCK mutations.
Adolescent↗
Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree.
Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus (NIDDM) associated with autosomal-dominant inheritance. In the RW pedigree, MODY is associated with polymorphic DNA markers on chromosome 20q. To determine the early abnormalities of insulin action and insulin secretion in MODY, we studied nondiabetic members of the RW pedigree with and without the gene marker. Six nondiabetic marker-negative and 5 nondiabetic marker-positive members of the RW pedigree were studied, as were 4 diabetic marker-positive family members. Unrelated, young, healthy subjects served as comparison groups. Insulin action and insulin secretion were assessed with a frequently sampled intravenous glucose tolerance test. Insulin secretion was further assessed during constant glucose infusion by deconvolution of plasma C-peptide and by pulse analysis. The nondiabetic marker-positive group had normal sensitivity to insulin and unimpaired acute insulin response to intravenous glucose (AIRglu). However, the nondiabetic marker-positive group had decreased mean plasma C-peptide concentration and reduced absolute amplitude of insulin secretory oscillations during prolonged glucose infusion. These responses to prolonged glucose infusion were similar to those observed in the diabetic group. No alterations of insulin secretion were observed in the nondiabetic marker-negative family members. Deranged and deficient insulin secretion, and not insulin resistance, appears to be the genetic or primary abnormality that characterizes nondiabetic individuals who are predisposed to MODY in the RW pedigree.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Compensation in pancreatic beta-cell function in subjects with glucokinase mutations.
The relationship between the in vivo insulin secretory responsiveness of the pancreatic beta-cell to glucose and the flux of glucose through the enzyme glucokinase was investigated in six subjects with heterozygous glucokinase mutations and in six matched control subjects. This was done by combining data published previously on the in vivo dose-response relationships between glucose and insulin secretion and on the in vitro enzymatic properties of wild-type and mutant forms of glucokinase. The flux of glucose through glucokinase (GK flux) in these subjects was estimated using a model based on the approximate Michaelis-Menten kinetics of wild-type and mutant forms of the enzyme. In two subjects with glucokinase mutations, which resulted in only a small reduction in enzymatic activity, the decrease in insulin secretion was directly proportional to the decrease in GK flux predicted using a Michaelis-Menten model for both mutant and wild-type glucokinase. However, in four subjects with glucokinase mutations, which resulted in severe reductions in enzymatic activity, insulin secretion was reduced compared with control subjects but less than predicted. This latter result implies the existence of a compensatory change in the beta-cells of such subjects, which results in a relative increase in insulin secretory response. We propose modifications to the simple model relating glucose concentration and GK flux, including glucose-induced overexpression of the normal allele and a role of glucokinase regulatory protein. The modifications take into account the possibility that the degree of compensation may be directly related to the severity of the mutation.
Adolescent↗
Molecular model of human beta-cell glucokinase built by analogy to the crystal structure of yeast hexokinase B.
Recent studies have shown that mutations in human beta-cell glucokinase that impair the activity of this key regulatory enzyme of glycolysis can cause early-onset non-insulin-dependent diabetes mellitus (NIDDM). The amino acid sequence of human glucokinase has 31% identity with yeast hexokinase, a related enzyme for which the crystal structure has been determined. This homology has allowed us to model the three-dimensional structure of human glucokinase by analogy to the crystal structure of yeast hexokinase B. This model of human glucokinase provides a basis for understanding the effects of mutations on its enzymatic activity. Residues in the active site and on the surface of the binding cleft for glucose are highly conserved in both enzymes. Regions far from the active site are predicted to differ in conformation, and 10 insertions or deletions that range in size from 1 to 7 residues are located on the protein surface between elements of secondary structure. The model structure suggests that human glucokinase binds glucose in a similar manner to yeast hexokinase. The glucose-binding site contains a conserved aspartic acid, two conserved glutamic acids, and two conserved asparagines that form hydrogen bond interactions with the hydroxyls of the glucose similar to those observed in other sugar-binding proteins. Mutation of residues in the predicted glucose-binding site has been found to greatly reduce enzymatic activity. This model will be useful for future structure/function studies of glucokinase.
Amino Acid Sequence↗
Molecular mechanisms of agonist-induced desensitization of the cloned mouse kappa opioid receptor.
Prolonged exposure of opioid receptors to agonists can cause desensitization, a cellular event linked to tolerance. Although evidence exists for mu and delta opioid receptor desensitization, much less information is available concerning the in vitro regulation of kappa opioid receptors because no cell lines exist that specifically express this class of opioid receptor. Recently we have cloned the mouse kappa opioid receptor. After expression in COS-7 cells, this protein exhibits the pharmacological specificity of a kappa 1 receptor and mediates agonist inhibition of cAMP formation. Continuous exposure of COS-7 cells expressing the kappa receptor to the agonist trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate salt (U50,488) reduces the specific binding of the kappa-selective agonist [3H]U69,593. Furthermore, the potency of U50,488 to inhibit the binding of the opiate antagonist [3H]naloxone to the kappa receptor is reduced. However, total specific binding of [3H]naloxone is not altered, indicating that short-term (2-4 hr) agonist treatment of the kappa receptor reduces the affinity of the receptor for agonists but does not reduce the density of kappa receptors. The reduction in affinity of the kappa receptor for agonists is dependent on the time of agonist exposure and is reversible. The reduced affinity of the receptor for agonists is associated with kappa receptor desensitization, because kappa receptor-mediated inhibition of cAMP formation is lost in cells pretreated with U50,488. The desensitization of the kappa receptor is dependent on the time and concentration of agonist treatment, is blocked by the kappa-selective antagonist nor-binaltorphimine and is reversible.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors.
Opioid drugs, such as morphine, and the endogenous opioid peptides, namely the enkephalins, endorphins, and dynorphins, exert a wide spectrum of physiological and behavioral effects, including effects on pain perception, mood, motor control, and autonomic functions. These effects are mediated via membrane-bound receptors, of which the best characterized are the kappa, delta, and mu receptors. The existence of these distinct types of opioid receptors has recently been confirmed by molecular cloning. In the present study, we have examined the pharmacological profiles of the cloned kappa, delta, and mu receptors using a battery of widely employed opioid agents. Our results suggest that the cloned kappa and mu receptors have pharmacological characteristics similar to those of the endogenously expressed kappa 1 and mu receptors, respectively. The cloned delta receptor displays a pharmacological profile consistent with that of a delta 2 receptor. Opioid agents with abuse potential possess high affinities for the mu receptor. The availability of the cloned receptors will facilitate the identification and development of more specific and selective compounds with greater therapeutic potential and fewer undesirable side effects.
Analgesics↗
Gi alpha 1 selectively couples somatostatin receptor subtype 3 to adenylyl cyclase: identification of the functional domains of this alpha subunit necessary for mediating the inhibition by somatostatin of cAMP formation.
A major cellular action of the neuropeptide somatostatin (SRIF) is the inhibition of adenylyl cyclase activity. SRIF induces this effect after its interaction with membrane-bound receptors. Five SRIF receptors (SSTRs), which differ in their functional coupling to adenylyl cyclase, have recently been cloned. The third SSTR cloned, SSTR3, effectively mediates the inhibition of adenylyl cyclase by SRIF. The molecular mechanism by which SRIF modulates intracellular cAMP synthesis via SSTR3 was investigated by initially identifying which G alpha subunits are involved in coupling SSTR3 to adenylyl cyclase. SRIF did not inhibit cAMP formation in Chinese hamster ovary cells stably expressing SSTR3 and Gi alpha 2 or Gi alpha 3 but lacking Gi alpha 1. However, SRIF did inhibit forskolin-stimulated cAMP formation in Chinese hamster ovary cells stably expressing SSTR3 and Gi alpha 1, indicating that Gi alpha 1 selectively couples SSTR3 to adenylyl cyclase. To investigate the functional domains of Gi alpha 1 necessary for interaction with SSTR3, a chimeric alpha subunit (Gi alpha 2/Gi alpha 1) was constructed, consisting of the amino-terminal two thirds of Gi alpha 2 ligated to the carboxyl-terminal third of Gi alpha 1. SRIF inhibited cAMP formation in cells expressing SSTR3 and the Gi alpha 2/Gi alpha 1 chimera. These findings indicate that the carboxy-terminal third of Gi alpha 1 interacts with SSTR3 and is important in transmitting the signal of SSTR3 activation to adenylyl cyclase. In contrast, a similar Gi alpha 2/Gi alpha 3 chimera did not couple SSTR3 to adenylyl cyclase, further indicating that Gi alpha 3 does not contribute to SRIF inhibition of adenylyl cyclase activity. These findings demonstrate that Gi alpha 1 selectively couples SSTR3 to adenylyl cyclase, and they indicate that the carboxyl-terminal region of this alpha subunit is involved in mediating SRIF inhibition of adenylyl cyclase activity.
Adenylyl Cyclases↗
Alternative splicing of human inwardly rectifying K+ channel ROMK1 mRNA.
Recent studies have identified a new family of inwardly rectifying K+ channels, members of which are known by the acronyms ROMK1, IRK1, and GIRK1. We have isolated cDNAs encoding the human homologue of ROMK1 from an adult kidney cDNA library. The sequences of the human kidney ROMK1 cDNA clones indicated that they were derived from at least two types of mRNAs, human ROMK1A and human ROMK1B, differing in sequence at their 5' ends. The isolation of the human ROMK1 gene, localized to chromosome band 11q24 by fluorescence in situ hybridization, indicated that the different ROMK1 transcripts were generated by alternative splicing. Human ROMK1A mRNA was predicted to encode a protein of 389 amino acids, having 93% identity with the 391-residue rat ROMK1 protein, and expression studies in Xenopus oocytes indicated that it encoded a Ba(2+)-sensitive inwardly rectifying K+ channel with properties similar to those reported for cloned rat ROMK1. Human ROMK1B mRNA was predicted to encode a protein of 372 amino acids whose sequence was truncated at the amino terminus but otherwise identical to that of the human ROMK1A protein. Translation of human ROMK1B mRNA was predicted to initiate at a codon corresponding to Met-18 of human ROMK1A mRNA. Reverse transcriptase-polymerase chain reaction amplification of human kidney mRNA revealed human ROMK1A and -B transcripts as well as a third type of transcript, human ROMK1C mRNA, which was predicted to encode a protein identical to human ROMK1B. Human ROMK1A, -B, and -C transcripts were identified in kidney, whereas only human ROMK1A mRNA could be detected in pancreatic islets and other tissues in which human ROMK1 was expressed at low levels. Thus, tissue-specific alternative splicing of human ROMK1 mRNA may result in the expression of a family of ROMK1 proteins.
Adult↗