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Endocrinology Vol. 138, No. 2 705-711
Copyright © 1997 by The Endocrine Society

Articles

Developmental and Tissue-Specific Sulfonylurea Receptor Gene Expression

Catalina Hernández-Sánchez, Teresa L. Wood and Derek LeRoith

Section on Molecular and Cellular Physiology, Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1770; and the Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine (T.L.W.), Hershey, Pennsylvania 17033

Address all correspondence and requests for reprints to: Dr. Catalina Hernández-Sánchez, Diabetes Branch, Room 8S235A, Building 10, National Institutes of Health, Bethesda, Maryland 20892-1770.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We have studied the developmental regulation of mouse sulfonylurea receptor (SUR) gene expression throughout several embryonic stages as well as in the adult mouse. To this end we used a 229-bp mouse complementary DNA corresponding to the 3'-end of the SUR gene for in situ hybridization and solution hybridization/ribonuclease protection assays. We found that the SUR gene was expressed as early as embryonic day 12 in the developing pancreas, heart, and central nervous system. These tissues maintained significant levels of SUR messenger RNA (mRNA) throughout development. In addition, SUR mRNA was detected in the submandibular gland, anterior duodenum, dorsal root ganglia, lens, retina, and vibrissae by late developmental stages.

SUR mRNA is widely distributed in adult mouse tissues, with the exception of the liver. In the adult pancreas, the SUR gene was expressed exclusively in endocrine tissue. Although significant levels of SUR mRNA were broadly seen throughout the brain, neurons of the cerebellum, hippocampus, and thalamus had especially high levels of SUR mRNA. These findings support the idea that the SUR has important functions in many other tissues in addition to the islets of the pancreas.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SULFONYLUREAS are insulin secretagogues widely used in the treatment of noninsulin-dependent diabetes mellitus. The binding of sulfonylurea to its receptor in the pancreatic ß-cell blocks the ATP-sensitive potassium channels (K+ATP channels) (1, 2). This block results in membrane depolarization that activates the voltage-dependent L-type Ca2+ channels and triggers Ca2+ influx and a rise in the intracellular Ca2+ concentration, initiating insulin secretion (3, 4, 5, 6). Recent evidence strongly suggests that the pancreatic ß-cell KATP channels are complexes composed of at least two subunits: the ß-cell inward rectifier family member, and the sulfonylurea receptor (SUR), a member of the ATP-binding cassette superfamily (7). SUR is a membrane protein with multiple transmembrane-spanning domains and two potential nucleotide-binding folds (NBF-1 and NBF-2) (8). Truncations of NBF-2 cause familial persistent hyperinsulinemic hypoglycemia of infancy characterized by unregulated secretion of insulin and profound hypoglycemia (9).

Although SUR appears to have a central role in the regulation of insulin secretion, its expression is not exclusive to the pancreatic islets. Sulfonylurea binding has been described in the heart (10, 11, 12, 13), brain (14, 15, 16), skeletal and smooth muscle (12, 16), as well as pancreatic ß-cells (14, 17, 18, 19). The regional distribution of sulfonylurea binding in the brain has been studied in several species of rodents and primates. High density sulfonylurea binding has been reported in the sensorimotor cortical areas, the caudate-putamen nuclei, and the molecular layer of the cerebellar cortex; all of them demonstrate some differences in subregional distribution (20). Despite these interesting studies on the distribution of sulfonylurea binding in the brain, very little is known about SUR gene expression in other tissues, and no studies have been reported in regard to embryonic expression and developmental regulation of SUR.

To better understand the possible biological role of SUR we studied SUR gene expression during development and in adult tissues using in situ hybridization and a solution hybridization/ribonuclease (RNase) protection assay. In this study we describe the developmental pattern of expression of SUR in the mouse and the specific pattern of expression in adult tissues. Particular emphasis has been placed on the regional expression of SUR in the adult brain.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Construction of the SUR riboprobe
A 229-bp fragment corresponding to a 3'-region of the mouse SUR complementary DNA (cDNA) including the putative NBF-2 domain (8) was generated by reverse transcription followed by PCR. Briefly, the reverse transcription (Boehringer Mannheim, Indianapolis, IN) reaction was performed with 3 µg mouse pancreas total RNA according to the manufacturer’s directions. A 229-bp PCR product was obtained with two primers based on the rat NBF-2 domain sequence and subcloned into a TA cloning vector (Invitrogen, San Diego, CA). Similarly, a 334-bp fragment corresponding to the 5'-region of the mouse SUR cDNA, including part of the N-terminal and the first two putative transmembrane domains (8), was obtained and subcloned into a TA cloning vector. The identity and orientation of the constructs were verified by sequence analysis. After linearization of the construct with EcoRV, the antisense RNA probe was generated using SP6 RNA polymerase. To generate a sense RNA probe, the construct was linearized with BamHI, and transcription was performed using T7 RNA polymerase.

Solution hybridization/RNase protection assay
Total RNA was prepared from tissues of 6-week-old male mice by the guanidinium thiocyanate-cesium chloride method (21). Briefly, mouse tissues were homogenized with a Polytron homogenizer (Brinkmann Instruments, Westbury, NY) in 4 M guanidinium isothiocyanate containing 0.01% ß-mercaptoethanol. The RNA was isolated by ultracentrifugation on a cesium chloride gradient as described previously. The RNA integrity was confirmed by visualization of the ethidium bromide-stained 28S and 18S ribosomal RNA bands. Polyadenylated [poly(A)+] RNA was prepared by oligo(deoxythymidine)-cellulose chromatography as previously described (22). Poly(A)+ RNA was quantified by measuring its absorbance at 260 nm. Approximately 5 µg poly(A)+ RNA from lung, spleen, and skeletal muscle and 10 µg from all other tissues were hybridized with 2 x 105 dpm of a mouse antisense SUR riboprobe. RNase protection assays were carried out as previously described (23).

In situ hybridization
35S-Labeled mouse sense and antisense SUR riboprobes were generated using T7 and SP6 polymerases, respectively, in the presence of CTP, GTP, ATP, and [35S]UTP. The resulting RNA transcripts were purified on Sephadex G-50 (Boehringer Mannheim) and used without hydrolysis. Frozen embryos and adult tissues that had been stored at -70 C were sectioned using a cryostat. Frozen sections (10 µm) were mounted onto Fisher Superfrost PLUS slides (Fisher Scientific, Fairlawn, NJ). The sections were postfixed for 10 min in 4% paraformaldehyde in PBS, rinsed in PBS, and dehydrated. Sections were acetylated, washed in 0.2 x SSC (1 x SSC contains 0.15 M NaCl and 0.015 M sodium citrate), and dehydrated. Sections were prehybridized for at least 2 h at room temperature in a solution containing 50% (vol/vol) deionized formamide, 0.6 M sodium chloride, 10 mM Tris (pH 7.5), 1 mM EDTA, 0.02% Ficoll, 0.02% BSA (fraction V), 0.02% polyvinylpyrrolidone, 0.5 mg/ml sheared herring sperm DNA, and 0.5 mg/ml yeast transfer RNA. Hybridization was carried out at 55 C overnight with 35S-labeled (4 x 104 cpm/µl) RNA probe in prehybridization buffer containing 10% dextran sulfate, 10 mM dithiothreitol, and 0.1% SDS. After hybridization, the sections were rinsed in 2 x SSC and washed for 30 min at 45 C with 50% deionized formamide in 1 x SSC plus 10 mM dithiothreitol followed by 30 min at room temperature in 0.5 x SSC. Unhybridized probe was removed by treatment with RNase A [100 µg/ml, in 0.5 M NaCl, 10 mM Tris (pH 7.5), and 1 mM EDTA] for 30 min at room temperature followed by a 2-h wash in 0.2 x SSC at 55 C. The sections were dehydrated through ethanol and exposed to autoradiographic film (Kodak Biomax MR, Eastman Kodak, Rochester, NY). After appropriate film exposure times (from 1–4 weeks) sections were coated with autoradiographic emulsion (Kodak NTB2) and stored at 4 C for 2–4 weeks before development, fixation, and counterstaining with hematoxylin.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
SUR gene expression in adult tissues: tissue distribution
To investigate the specific tissue distribution of SUR messenger RNA (mRNA) in adult tissues, poly(A)+ RNA was extracted from a wide number of tissues, including adipose tissue, brain, heart, intestine, kidney, liver, lung, pancreas, skeletal muscle, spleen, stomach, and testis. The solution hybridization/RNase protection assay was carried out, as described in Materials and Methods, with the 3'-region riboprobe. All tissues except liver expressed significant amounts of SUR mRNA (Fig. 1Go). High SUR gene expression was found in brain and heart, whereas SUR mRNA was barely detectable in spleen. We could not detect SUR mRNA in liver despite using this sensitive method with prolonged exposures. The quality of the liver poly(A)+ RNA was verified by a solution hybridization/RNase protection assay of the mouse ß-actin (data not shown).



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  		Figure 1. SUR mRNA distribution in adult tissues. Solution hybridization/RNase protection assay was performed with 5 µg poly(A)+ RNA from lung, spleen, and skeletal muscle and 10 µg from the remaining tissues. Ten micrograms of total RNA from a mouse pancreatic ß-cell line (ßTC3) were used as a positive control.

 
Expression of the SUR gene by in situ hybridization
To more precisely identify sites of SUR gene expression, we used in situ hybridization with the 3'-region riboprobe to localize SUR mRNA in sections from mouse embryos on embryonic days 12 (E12), 14/15, and 18; from neonates on postnatal day 1 (P1); and from adult brain and pancreas.

SUR gene expression at embryonic stages.
SUR mRNA was detected at the earliest age examined, E12, in the pancreatic primordium, developing heart, and spinal cord (Fig. 2Go, A and B). SUR gene expression persisted in pancreas, heart, and central nervous system (CNS) throughout embryonic development (Fig. 2Go). By mid- to late gestational ages, SUR gene expression also was apparent in the submandibular gland (Fig. 2FGo), the lumen of the anterior duodenum (Fig. 2Go, E and F), and the dorsal root ganglia (Fig. 2FGo). On P1, SUR mRNA was detected at additional sites, including the lens, retina (Fig. 3Go), and vibrissae (data not shown).



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  		Figure 2. SUR gene expression during mouse embryonic development. Autoradiographic film exposures of different embryonic stages. A and B, Sagittal section of an E12 embryo. C, Sagittal section of an E14/15 embryo. D, Transverse section of an E14/15 embryo. E and F, Sagittal sections of E18 embryo. h, Heart; p, pancreatic primordium; ad, anterior duodenum; sc, spinal cord; nc, neopallial cortex; th, thalamus; rp, roof plate, fp; floor plate; vm, ventral mantle zone; smg, submandibular gland; drg, dorsal root ganglia; ob, olfactory bulb; pi, pituitary. The hybridization with the respective sense probe showed no hybridization signal (data not shown). Bar = 500 µm.

 


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  		Figure 3. SUR gene expression in the eye on day P1. Autoradiographic emulsion exposures. A and B, Bright- and darkfield views, respectively, of eye on P1. pe, Pigmentarium epithelium; r, retina; v, vitreous; l, lens. Bar = 200 µm.

 
SUR mRNA in the developing and adult CNS.
By E14/15, expression of SUR in the spinal cord became localized to the floor plate and the ventral mantle zones, including regions of developing motor neurons, with lower levels of hybridization detected in the roof plate (Fig. 2DGo). In addition, the dorsal root ganglia were beginning to show positive hybridization, which became more prominent on E18 (Fig. 2FGo) and P1 (data not shown). Expression of SUR in more anterior regions of the CNS was apparent by E14/15 and was particularly prominent in the neopallial cortex and developing thalamus (Fig. 2CGo). By E18, the developing hippocampus and regions of the cerebral cortex derived from the neopallial cortex showed high levels of SUR gene expression (Fig. 2Go, E and F). SUR mRNA also was detected on E18 in the olfactory bulb, specifically in the mitral cell layer (Fig. 2FGo), in regions of the developing thalamus (Fig. 2EGo), and in the trigeminal ganglion (data not shown). In addition, expression in the developing pituitary was first apparent at this age (Fig. 2FGo). On P1, SUR gene expression was detected in the inner plexiform layer of the retina and in the lens (Fig. 3Go).

To determine the regional distribution of SUR mRNA in the adult brain, we performed in situ hybridization in P21 and P42 mouse brains. At both ages, the SUR gene expression pattern was essentially identical. Significant levels of SUR mRNA were seen throughout the whole brain, with especially high levels in the cerebellum and hippocampal regions (Fig. 4Go). In the cerebellum, granule neurons were strongly positive for SUR mRNA expression, as were the Purkinje neurons and neurons of the medial cerebellar nuclei (Fig. 4Go, B, C, and D). SUR mRNA in the hippocampus was detected in the pyramidal neurons of CA1 through CA3 and in the granule neurons of the dentate gyrus (Fig. 4Go, B and E). Hybridization was also observed in cells scattered throughout the brain, but was particularly prominent in the occipital and retrosplenial cortex and the thalamic nuclei, especially the anterodorsal thalamic nucleus and the pontine nucleus (Fig. 4Go, A and F). The large, pale, hematoxylin-stained nuclei of the positive cells in these regions suggests that they most likely correspond to neurons. In the adult pituitary gland, the SUR hybridization signal was evenly distributed in the anterior lobe, with no signal detected in either the intermediate or posterior lobes (Fig. 5Go).



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  		Figure 4. SUR gene expression in the adult brain. Autoradiographic emulsion exposures of P42 brain sagittal sections. A, SUR sense hybridization; B, SUR antisense hybridization. C and D, Cerebellum bright- and darkfield views, respectively. E, Hippocampus; F, thalamus. hp, Hippocampus; oc, occipital cortex; th, thalamus; cb cerebellar cortex; mcn, medial cerebellar nuclei; pn, pontine nucleus; dg, dentate gyrus; gr, granular layer; pk, Purkinje cells. Bar = 500 µm for A and B; 100 µm for C, D, and E; and 50 µm for F.

 


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  		Figure 5. SUR gene expression in pituitary. Autoradiographic emulsion exposures of sagittal sections of the pituitary. A and B, Bright- and darkfield views, respectively. al, Anterior lobe; il, intermedia lobe; pl posterior lobe. Bar = 100 µm.

 
SUR gene expression in pancreas.
By far the highest level of expression at E12 was in the pancreatic primordium, with significant hybridization also detected in adjacent gut epithelium (Fig. 2BGo). Expression of SUR mRNA was maintained at high levels in the pancreatic primordium throughout embryonic stages (Fig. 6Go, A and B). In the P42 adult pancreas, the SUR gene was expressed in a focal pattern in the amacrine pancreas, but was absent in the exocrine tissue, supporting the hypothesis that SUR is specifically expressed in pancreatic islets cells (Fig. 6EGo and F).



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  		Figure 6. SUR gene expression in pancreas. A and B, Transverse sections of E14/15 embryos; bright- and darkfield views, respectively, of autoradiographic emulsion exposures. C and D, P42 pancreas, SUR sense and antisense hybridization, respectively (autoradiographic film exposures). E and F, P42 pancreas, SUR hybridization (autoradiographic emulsion exposures). l, Liver; ad, anterior duodenum. Bar = 100 µm for A and B, 500 µm for C and D, and 50 µm for E and F.

 
Identical results were obtained using the riboprobe against the 5'-region of the mouse SUR mRNA (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Although sulfonylureas are commonly used in the treatment of noninsulin-dependent diabetes mellitus, very little is known about the developmental regulation of SUR expression and its distribution in adult tissues. In the present study we have shown that SUR gene expression is developmentally regulated, and SUR mRNA is widely distributed in the adult mouse. SUR mRNA was detected as early as E12 (the earliest stage examined). At this stage the pancreatic primordium contained the highest levels of SUR gene expression and maintained high levels throughout the course of development. In the adult pancreas the focal pattern of SUR expression suggests that SUR mRNA is present exclusively in the endocrine pancreas in accordance with its role in the regulation of insulin secretion from pancreatic ß-cells (1, 2). Homogeneous distribution of SUR mRNA was detected in the developing heart from E12 through early postnatal life. This is in accord with a study by Miller et al. (13) that showed nearly uniform distribution of sulfonylurea-binding sites in the adult rat heart.

The CNS demonstrates an interesting pattern of SUR gene expression during embryonic and postnatal ontogeny. On E12, SUR mRNA is prominent in the floor plate and ventral mantle zones of the spinal cord. Studies by Mourre et al. (24) and Miller et al. (13) have shown equivalent amounts of sulfonylurea binding in the posterior and anterior horns of the spinal cord in the adult rat, with a rostral to caudal gradient. In brain, SUR mRNA was initially detected at midgestation stages. SUR gene expression increased in the brain by late gestational stages and these high levels were maintained in the adult brain. The neopallial cortex exhibited the highest SUR mRNA hybridization signal during embryonic development, whereas in the adult brain the hippocampus and cerebellum showed the highest levels of hybridization. In addition, significant SUR mRNA levels were detected throughout the adult brain. A similar general pattern of distribution of sulfonylurea binding was reported previously by Mourre et al. (24), Miller et al. (13), and Zini et al. (20). High levels of sulfonylurea binding were reported in both the hippocampal formation and the cerebellum, regions where we observed the highest SUR mRNA levels. The sites of receptor mRNA synthesis closely correlated with the sulfonylurea-binding sites in the hippocampus and dentate gyrus. In the cerebellum, however, the highest density of binding sites was reported in the molecular layer (13, 20, 24), whereas we observed the strongest hybridization signal to SUR mRNA over the granule and Purkinje cell layers. Analysis of sulfonylurea-binding sites in the cerebellar mutant mice by Mourre et al. (24) led to the conclusion that the binding was predominantly associated with parallel fibers, the axons of the granule neurons. Together with the dendritic trees of the Purkinje cells on which they synapse, the parallel fibers are a large component of the cerebellar molecular layer. These results are consistent with our observation that the primary sites of receptor mRNA synthesis are the cell bodies of the granule and Purkinje neurons.

Although most other brain regions, including the cortex, thalamus, and pituitary, where high ligand binding was reported, were also sites where we observed significant SUR mRNA synthesis, there were two notable exceptions. The substantia nigra and the globus pallidus both showed strikingly high levels of sulfonylurea-binding sites (13, 20, 24), whereas we observed only moderate levels of hybridization to SUR mRNA at these sites. It is possible that, like that in the cerebellum, the location of binding sites in these regions represents concentration of the protein on axons projecting from other regions. On another hand, the existence of other SUR isoforms may account for this discrepancy. Recently, another member of the SUR family have been described (25, 26). SUR2 mRNA was shown to be widely expressed in embryonic tissues, with very high levels in heart and smooth muscle. In most of the other tissues, SUR2 mRNA was seen in areas corresponding to vascular structures. This expression pattern is distinct from the SUR expression that is shown in this paper with two different probes.

Although many tissues display SUR gene expression in the adult mouse, the biological function of SUR in each particular tissue and cell type remains unclear. To date it has been postulated that SUR is involved in the regulation of the K+ATP channel activity. The K+ATP channels are considered a close link between the metabolism of a cell and its excitability. For instance, in the unstimulated pancreatic ß-cell the K+ATP channels are involved in maintaining the resting membrane potential (27). Closure of the K+ATP channel after increased glucose uptake and metabolism, associated with an increase in the ATP/ADP ratio, leads to membrane depolarization that results in activation of the L-type voltage-gated Ca2+ channel and an increase in the intracellular levels of free Ca2+ and culminates with insulin secretion. Although it has been established that sulfonylureas stimulate insulin secretion by blocking the K+ATP channels, other mechanisms may also be involved. Recently, Eliasson et al. (28) have shown that sulfonylureas stimulate exocytosis in pancreatic ß-cells interacting directly with the secretory machinery by a mechanism dependent on protein kinase C which may not involve the plasma membrane K+ATP channel. The central role of SUR in insulin secretion has been confirmed by the characterization of mutations in the human SUR gene that are associated with the familial persistent hyperinsulinemic hypoglycemia of infancy (9). Analysis of point mutations in the NBF-2 of SUR reveal a functional role of SUR in nucleotide regulation of K+ATP channel activity and propose ADP as the physiological regulator of the channel activity (29).

In the brain, the K+ATP channel has been shown to be involved in the control of neurotransmitter release. Amoroso et al. (30) have shown that sulfonylureas stimulate {gamma}-aminobutyric acid secretion in substantia nigra slices in a dose-dependent manner. Similarly, it has been suggested that sulfonylureas may have a role in GH release in the pituitary (31). It has been proposed that the K+ATP channel in the brain may be involved in a cytoprotective response to ischemia and anoxia. Cerebral anoxia and ischemia elicit neural hyperpolarization due to activation of the K+ATP channels (2). This response can be blocked by the addition of sulfonylureas (32, 33, 34, 35). Similarly, the K+ATP channels are involved in the cellular response to cardiac ischemia (2). Moreover, the biological functions of SUR may be even more diverse than described above, as it has been shown that SUR can confer sulfonylurea sensitivity to a variety of inward-rectifying K+ channels as well as to the K+ATP channels (36).

The biological role of SUR during embryogenesis remains unknown. In the pancreas at least, SUR is probably involved in insulin secretion even at early stages. In mice, the ß-cells appear in the pancreatic primordium on approximately E10.5, whereas insulin immunoreactivity has been detected in the ß-cells on E11 (37). The presence of SUR mRNA in the developing pancreas on E12 may indicate that SUR is also involved in the regulation of insulin secretion from the pancreatic primordium during embryonic development.

To date very little is known about the nature and distribution of the endogenous ligand for SUR. However, Virsolvy-Vergine et al. (38, 39) have purified two small peptide molecules, called endosulfine {alpha} and ß, that may act as endogenous ligands.

In summary, we have shown that the SUR gene is expressed during embryonic development and is broadly distributed in adult tissues. Further experiments are required to determine its role during development and in nonpancreatic adult tissues.


   Acknowledgments
 
We thank Dr. Simeon Taylor for his suggestions, Dr. Marc Reitman for his help with cloning the mouse SUR cDNA, Dr. Greti Aguilera’s laboratory for use of their equipment, and Drs. Vicky Blakesley and Rick Reinhart for critical review of the manuscript.

Received July 19, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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