Biomedical subjects

L H Philipson

Publications and source records attributed to L H Philipson.

At least 19 recordsLinked to original sources

PubMed2007

TRP channels of the pancreatic beta cell.

Orchestrated ion fluctuations within pancreatic islets regulate hormone secretion and maybe essential to processes such as apoptosis. A diverse set of ion channels allows for islet cells to respond to a variety of signals and dynamically regulate hormone secretion and glucose homeostasis (reviewed by Houamed et al. 2004). This chapter focuses on transient receptor potential (TRP)-related channels found within the beta cells of the islet and reviews their roles in both insulin secretion and apoptosis.

Animals↗

PubMed2006

Reactive species and early manifestation of insulin resistance in type 2 diabetes.

The early stages of type 2 diabetes mellitus are characterized by the development of insulin resistance (IRe) in muscle cells and adipocytes with the concomitant loss of beta-cell compensation. We have extensively reviewed the literature related to metabolic and signalling pathways of reactive oxygen species (ROS) in regard to the coordinated development of oxidative stress and IRe. We considered the hypothesis that oxidative stress leads to IRe in muscle cells and adipocytes, but found that the data are more consistent with the hypothesis that the cellular mechanisms that protect against oxidative stress per se are capable of creating an ROS-dependent insulin-resistant state. Furthermore, ROS-induced mitochondrial dysfunction can lead to disruptions of lipid metabolism, increasing the intracellular lipid content, and, in addition, contribute to lipid-dependent IRe in myocytes. Together, these two ROS-activated pathways to IRe can contribute to a global state of profound resistance to insulin action. Therapeutic strategies should, therefore, be directed towards reducing insulin resistance without an increase in ROS production or concentration. Pharmacological or other approaches to IRe that result in the activation of mitochondrial biogenesis in particular could be highly beneficial in the prevention or treatment of both insulin resistance and type 2 diabetes.

Adipocytes↗

PubMed2006

Improved outcomes in islet isolation and transplantation by the use of a novel hemoglobin-based O2 carrier.

During isolation, islets are exposed to warm ischemia. In this study, intraductal administration of oxygenated polymerized, stroma-free hemoglobin-pyridoxalated (Poly SFH-P) was performed to improve O2 delivery. Rat pancreata subjected to 30-min warm ischemia were perfused intraductally with collagenase in oxygenated Poly SFH-P/RPMI or RPMI (control). PO2 was increased by Poly SFH-P (381.7 +/- 35.3 mmHg vs. 202.3 +/- 28.2, p = 0.01) and pH maintained within physiological range (7.4-7.2 vs. 7.1-6.6, p = 0.009). Islet viability (77% +/- 4.6 vs. 63% +/- 4.7, p = 0.04) was improved and apoptosis lower with Poly SFH-P (caspase-3: 34,714 +/- 2167 vs. 45,985 +/- 1382, respectively, p = 0.01). Poly SFH-P improved islet responsiveness to glucose as determined by increased intracellular Ca2+ levels and improved insulin secretion (SI 5.4 +/- 0.1 vs. 3.1 +/- 0.2, p = 0.03). Mitochondrial integrity was improved in Poly SFH-P-treated islets, which showed higher percentage change in membrane potential after glucose stimulation (14.7% +/- 1.8 vs. 9.8 +/- 1.4, respectively, p < 0.05). O2 delivery by Poly SFH-P did not increase oxidative stress (GSH 7.1 +/- 2.9 nm/mg protein for Poly SFH-P vs. 6.8 +/- 2.4 control, p = 0.9) or oxidative injury (MDA 1.8 +/- 0.9 nmol/mg protein vs. 6.2 +/- 2.4, p = 0.19). Time to reach normoglycemia in transplanted diabetic nude mice was shorter (1.8 +/- 0.4 vs. 7 +/- 2.5 days, p = 0.02), and glucose tolerance improved in the Poly SFH-P group (AUC 8106 +/- 590 vs. 10,863 +/- 946, p = 0.03). Oxygenated Poly SFH-P improves islet isolation and transplantation outcomes by preserving mitochondrial integrity.

Animals↗

PubMed2005

Intragranular targeting of syncollin, but not a syncollinGFP chimera, inhibits regulated insulin exocytosis in pancreatic beta-cells.

Several proteins play a role in the mechanism of insulin exocytosis. However, these 'exocytotic proteins' have yet to account for the regulated aspect of insulin exocytosis, and other factors are involved. In pancreatic exocrine cells, the intralumenal zymogen granule protein, syncollin, is required for efficient regulated exocytosis, but it is not known whether intragranular peptides similarly influence regulated insulin exocytosis. Here, this issue has been addressed using expression of syncollin and a syncollin-green fluorescent protein (syncollinGFP) chimera in rat islet beta-cells as experimental tools. Syncollin is not normally expressed in beta-cells but adenoviral-mediated expression of both syncollin and syncollinGFP indicated that these were specifically targeted to the lumen of beta-granules. Syncollin expression in isolated rat islets had no effect on basal insulin secretion but significantly inhibited regulated insulin secretion stimulated by glucose (16.7 mM), glucagon-like peptide-1 (GLP-1) (10 nM) and glyburide (5 microM). Consistent with specific localization of syncollin to beta-granules, constitutive secretion was unchanged by syncollin expression in rat islets. Syncollin-mediated inhibition of insulin secretion was not due to inadequate insulin production. Moreover, secretagogue-induced increases in cytosolic intracellular Ca2+, which is a prerequisite for triggering insulin exocytosis, were unaffected in syncollin-expressing islets. Therefore, syncollin was most likely acting downstream of secondary signals at the level of insulin exocytosis. Thus, syncollin expression in beta-cells has highlighted the importance of intralumenal beta-granule peptide factors playing a role in the control of insulin exocytosis. In contrast to syncollin, syncollinGFP had no effect on insulin secretion, underlining its usefulness as a 'fluorescent tag' to track beta-granule transport and exocytosis in real time.

Animals↗

PubMed2002

beta-Agonists and metabolism.

This review presents recent concepts of how beta-agonists affect glucose homeostasis by modulating insulin secretion, liver metabolism, and uptake of glucose into muscle, with attention to the influence of hypoglycemia on beta-agonist sensitivity and the effects of beta(3)-adrenergic receptor (beta(3)AR) polymorphisms on adipocyte metabolism. Specific beta(2)-agonist effects on the pancreatic beta cell result in increased insulin secretion, yet other mechanisms, such as increased glucagon secretion and hepatic effects, cause an overall increase in serum glucose and an apparent decrease in insulin sensitivity. Human studies confirm the presence of beta(2)ARs on pancreatic beta cells. Intensive treatment of diabetes mellitus with insulin, especially in type 1 diabetes, has led to increased incidence of hypoglycemia. Repeated episodes of hypoglycemia lead to unawareness of neuroglycopenia, a major limitation to intensive treatment. Hypoglycemic unawareness is associated with reduced beta-agonist sensitivity. Scrupulous avoidance of hypoglycemia over many weeks to months can restore beta-agonist sensitivity and improve detection of hypoglycemia. beta-agonists have also been employed to prevent hypoglycemia. beta-agonists can increase thermogenesis and lipolysis, leading to increased energy expenditure and decreased fat stores. While beta(1)ARs and beta(2)ARs mediate many of these actions, it is likely that beta(3)ARs in the adipocyte membrane also play an important role. Specific beta(3)AR subtypes have been associated with obesity and the metabolic syndrome.

Adipose Tissue↗

PubMed2000

The status of voltage-dependent calcium channels in alpha 1E knock-out mice.

It has been hypothesized that R-type Ca currents result from the expression of the alpha(1E) gene. To test this hypothesis we examined the properties of voltage-dependent Ca channels in mice in which the alpha(1E) Ca channel subunit had been deleted. Application of omega-conotoxin GVIA, omega-agatoxin IVA, and nimodipine to cultured cerebellar granule neurons from wild-type mice inhibited components of the whole-cell Ba current, leaving a "residual" R current with an amplitude of approximately 30% of the total Ba current. A minor portion of this R current was inhibited by the alpha(1E)-selective toxin SNX-482, indicating that it resulted from the expression of alpha(1E). However, the majority of the R current was not inhibited by SNX-482. The SNX-482-sensitive portion of the granule cell R current was absent from alpha(1E) knock-out mice. We also identified a subpopulation of dorsal root ganglion (DRG) neurons from wild-type mice that expressed an SNX-482-sensitive component of the R current. However as with granule cells, most of the DRG R current was not blocked by SNX-482. We conclude that there exists a component of the R current that results from the expression of the alpha(1E) Ca channel subunit but that the majority of R currents must result from the expression of other Ca channel alpha subunits.

Animals↗

PubMed2000

Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion.

To study effects of Bcl-x(L) in the pancreatic beta-cell, two transgenic lines were produced using different forms of the rat insulin promoter. Bcl-x(L) expression in beta-cells was increased 2- to 3-fold in founder (Fd) 1 and over 10-fold in Fd 2 compared with littermate controls. After exposure to thapsigargin (10 microM for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl-x(L) transgenic mice were significantly lower than in islets of wild-type mice. Unexpectedly, severe glucose intolerance was observed in Fd 2 but not Fd 1 Bcl-x(L) mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However, Fd 2 Bcl-x(L) islets had impaired insulin secretory and intracellular free Ca(2+) ([Ca(2+)](i)) responses to glucose and KCl. Furthermore, insulin and [Ca(2+)](i) responses to pyruvate methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-x(L) islets. Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-x(L) islets than in wild-type islets. Glucose-, PME-, and alpha-ketoisocaproate-induced hyperpolarization of mitochondrial membrane potential, NAD(P)H, and ATP production were also significantly reduced in Fd 2 Bcl-x(L) islets. Thus, although Bcl-x(L) promotes beta-cell survival, high levels of expression of Bcl-x(L) result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for insulin secretion.

Animals↗

PubMed2000

Baculovirus-mediated gene transfer into pancreatic islet cells.

Baculovirus transduction is a gene transfer method that uses a moth cell virus for mammalian cells in culture, which results in a high-level prolonged expression. Here we demonstrate that recombinant baculoviruses can serve as efficient gene transfer vehicles for delivering foreign genes driven by mammalian promoters into human and mouse pancreatic islet cells. Existing methods, such as various transfection and electroporation techniques, either suffer from low efficiency or cause extensive membrane damage. Viral vectors have emerged as an important tool for gene delivery and expression in mammalian cells but suffer from several drawbacks, such as lengthy construction time and expression of viral genes. The baculovirus Autographa californica multiple nuclear polyhedrosis virus is widely used as a vector for expression of foreign genes in insect cells and, more recently, in some mammalian cells. Using several green fluorescent protein- and LacZ-expressing constructs in a cytomegalovirus promoter cassette, we obtained efficient gene expression in primary human and mouse islet cells. There was no impairment of glucose-stimulated intracellular free calcium responses after baculovirus infection. The safety and the relative ease of construction and propagation of the virus makes the baculovirus system a useful tool for facilitating the transfer of foreign genes.

Animals↗

PubMed1999

Beta-cell ion channels: keys to endodermal excitability.

Whereas pancreatic islet cells are not neurons, they are endodermally-derived specialized excitable cells that display many properties of neurons. Multiple ion channels in the pancreatic beta-cell regulate electrical excitability. Our focus for the last several years has been on the delayed rectifier (Kv) K+ channels, in an effort to define the individual roles of specific Kv channel genes in the overall regulation of insulin secretion. The many Kv channel genes, represented by more than 40 mammalian isoforms (termed Kv1 to Kv8), give rise to overlapping functions, primarily regulating repolarization of the plasma membrane. Experiments involving inhibition of Kv channel function have shown the important role Kv channels play in regulating beta-cell calcium oscillations in response to glucose stimulation. From our recent studies, we have concluded that although detectable mRNA for Kv1 family members is present in islets, Kv1 family channels are unlikely to play a significant role in the beta-cell, and we are now focusing on the roles of Kv2 and Kv3 channels.

Delayed Rectifier Potassium Channels↗

PubMed1998

Characterization of a Ca2+ release-activated nonselective cation current regulating membrane potential and [Ca2+]i oscillations in transgenically derived beta-cells.

Although stimulation of insulin secretion by glucose is regulated by coupled oscillations of membrane potential and intracellular Ca2+ ([Ca2+]i), the membrane events regulating these oscillations are incompletely understood. In the presence of glucose and tetraethylammonium, transgenically derived beta-cells (betaTC3-neo) exhibit coupled voltage and [Ca2+]i oscillations strikingly similar to those observed in normal islets in response to glucose. Using these cells as a model system, we investigated the membrane conductance underlying these oscillations. Alterations in delayed rectifier or Ca2+-activated K+ channels were excluded as a source of the conductance oscillations, as they are completely blocked by tetraethylammonium. ATP-sensitive K+ channels were also excluded, since the ATP-sensitive K+ channel blocker tolbutamide substituted for glucose in inducing [Ca2+]i oscillations. Thapsigargin, which depletes intracellular Ca2+ stores, and maitotoxin, an activator of nonselective cation channels, both converted the glucose-dependent [Ca2+]i oscillations into a sustained elevation. On the other hand, both SKF 96365, a blocker of Ca2+ store-operated channels, and external Na+ removal suppressed the glucose-stimulated [Ca2+]i oscillations. Maitotoxin activated a nonselective cation current in betaTC3 cells that was attenuated by removal of extracellular Na+ and by SKF 96365, in the same manner to a current activated in mouse beta-cells following depletion of intracellular Ca2+ stores. Currents similar to these are produced by the mammalian trp-related channels, a gene family that includes Ca2+ store-operated channels and inositol 1,4,5-trisphosphate-activated channels. We found several of the trp family genes were expressed in betaTC3 cells by reverse transcriptase polymerase chain reaction using specific primers, but by Northern blot analysis, mtrp-4 was the predominant message expressed. We conclude that a conductance underlying glucose-stimulated oscillations in beta-cells is provided by a Ca2+ store depletion-activated nonselective cation current, which is plausibly encoded by homologs of trp genes.

Animals↗

PubMed1998

Regulation of K+ and Ca++ channels by a family of neuropeptide Y receptors.

We examined the ability of rat Y1, Y2 and Y4 neuropeptide Y (NPY) receptors to regulate K+ and Ca++ channels expressed in Xenopus oocytes and HEK 293 cells, respectively. Stimulation of all three receptors with NPY or related peptides activated inwardly rectifying K+ currents resulting from the expression of rat GIRK1/CIR in frog oocytes. These effects were inhibited by pertussis toxin treatment. The effects of activating Y1 receptors were antagonized competitively by BIBP3226, SR120819A and GW1229. The effects of Y2 receptor activation were not blocked by these drugs, and the effects of Y4 receptor activation were only blocked by GW1229. Activation of all three NPY receptors also inhibited human alpha-1B Ca++ channels stably expressed in HEK293 cells. The effects of agonists at all three receptors were blocked by pertussis toxin treatment and were voltage dependent. Activation of all three types of NPY receptors produced much smaller inhibition of human alpha-1E Ca++ channels also stably expressed in HEK293 cells. These results suggest that NPY receptors can regulate K+ and Ca++ channels and that these effects may be responsible for the observed effects of NPY on neuronal excitability and synaptic transmission.

Animals↗

PubMed1997

Cloning, expression, and chromosomal mapping of a novel human CC-chemokine receptor (CCR10) that displays high-affinity binding for MCP-1 and MCP-3.

Chemokines mediate their chemotactic, proinflammatory effects by binding to and activating a variety of specific receptors belonging to the G protein-coupled superfamily of seven-transmembrane serpentine receptors. We report the cloning, chromosomal localization, expression, and ligand binding of a novel CC chemokine receptor, CCR10. CCR10 is expressed primarily in placenta and fetal liver, and binds two of the CC chemokines, monocyte chemoattractant protein (MCP)-1 and MCP-3, with highest affinity. The KD for MCP-3 binding was 1 nM, and MCP-1 competed for MCP-3 binding with an IC50 of 1.2 nM. The CC chemokines MCP-4 and RANTES competed for MCP-3 binding with IC50 values of 7.5 and 5.4 nM, respectively. The chromosomal location of CCR10 was determined to coincide with the CC chemokine receptor cluster on chromosome 3 (3p21.31-3p21.32). These results indicate that CCR10 is a novel CC chemokine receptor with a unique expression pattern that would be consistent with a role in placental immunity or hematopoiesis.

Amino Acid Sequence↗

PubMed1996

Expression and function of pancreatic beta-cell delayed rectifier K+ channels. Role in stimulus-secretion coupling.

Voltage-dependent delayed rectifier K+ channels regulate aspects of both stimulus-secretion and excitation-contraction coupling, but assigning specific roles to these channels has proved problematic. Using transgenically derived insulinoma cells (betaTC3-neo) and beta-cells purified from rodent pancreatic islets of Langerhans, we studied the expression and role of delayed rectifiers in glucose-stimulated insulin secretion. Using reverse-transcription polymerase chain reaction methods to amplify all known candidate delayed rectifier transcripts, the expression of the K+ channel gene Kv2.1 in betaTC3-neo insulinoma cells and purified rodent pancreatic beta-cells was detected and confirmed by immunoblotting in the insulinoma cells. betaTC3-neo cells were also found to express a related K+ channel, Kv3.2. Whole-cell patch clamp demonstrated the presence of delayed rectifier K+ currents inhibited by tetraethylammonium (TEA) and 4-aminopyridine, with similar Kd values to that of Kv2.1, correlating delayed rectifier gene expression with the K+ currents. The effect of these blockers on intracellular Ca2+ concentration ([Ca2+]i) was studied with fura-2 microspectrofluorimetry and imaging techniques. In the absence of glucose, exposure to TEA (1-20 mM) had minimal effects on betaTC3-neo or rodent islet [Ca2+]i, but in the presence of glucose, TEA activated large amplitude [Ca2+]i oscillations. In the insulinoma cells the TEA-induced [Ca2+]i oscillations were driven by synchronous oscillations in membrane potential, resulting in a 4-fold potentiation of insulin secretion. Activation of specific delayed rectifier K+ channels can therefore suppress stimulus-secretion coupling by damping oscillations in membrane potential and [Ca2+]i and thereby regulate secretion. These studies implicate previously uncharacterized beta-cell delayed rectifier K+ channels in the regulation of membrane repolarization, [Ca2+]i, and insulin secretion.

4-Aminopyridine↗

PubMed1996

Selective G-protein regulation of neuronal calcium channels.

We examined the properties and regulation of Ca channels resulting from the expression of human alpha1B and alpha1E subunits stably expressed in KEK293 cells. The ancillary subunits beta1B and alpha2/delta were also stably expressed in these cell lines. Ca currents in alpha1B-expressing cells had the properties of N-type currents. Ca currents in cells expressing alpha1E exhibited a novel profile that was similar to the properties of the "R type" Ca current. Introduction of GTP-gamma-S into alpha1B cells greatly enhanced the extent of prepulse facilitation of the Ca current, whereas it had only a very small effect in alpha1E-expressing cells. Activation of somatostatin receptors endogenous to HEK293 cells or kappa opioid receptors, expressed in the cells after transfection, inhibited Ca currents in alpha1B-expressing cells. This inhibition was blocked by pertussis toxin and was partially relieved by a depolarizing prepulse. In contrast, no inhibitory effects were noted in cells expressing alpha1E channels under the same circumstances. HEK293 cells normally contained G-proteins from all of the four major families. Inhibition of Ca currents by kappa agonists in alpha1B-expressing cells was enhanced slightly by the cotransfection of several G-protein alpha subunits. kappa agonists, however, had no effect in alpha1E-containing cells, even after overexpression of different G-protein alpha-subunits. In summary, these results demonstrate that there is a large difference in the susceptibility of alpha1B- and alpha1E-based Ca channels to regulation by G-proteins. This is so despite the fact that the two types of Ca channels show substantial similarities in their primary sequences.

Calcium Channels↗

PubMed1996

N-type inactivation in the mammalian Shaker K+ channel Kv1.4.

Mammalian voltage-gated K+ channels are oligomeric proteins, some of which may be composed in vivo of subunits derived from several similar genes. We have studied N-type inactivation in the rapidly inactivating Kv1.4 channel and, in specific, heteromultimers of this gene product with Kv1.5 noninactivating subunits. Heteromultimeric channels were analyzed for the stoichiometry of Kv1.4:Kv1.5 subunits by observing shifts in the midpoints of steady-state availability from that of homomultimeric channels. This analysis was employed to examine inactivation of heteromultimeric channels expressed in Xenopus oocytes using two model systems: by expression of a Kv1. 4-Kv1.5 tandem fusion construct and by coexpression of native Kv1.4 and Kv1.5 channels across a wide relative concentration range of microinjected mRNA. Additionally, inactivation was examined in coexpression experiments of N-terminal deletion mutants of Kv1.4. We found that (i) a single inactivating subunit conferred inactivation in all hetero-multimers studied; (ii) the rate of inactivation could not be distinguished in channels containing two inactivating subunits from those containing one inactivating subunit; and (iii) large deletions in the linker region between the N-terminal inactivation region and the first membrane-spanning domain had no effect on the rate of inactivation. These data confirm the importance of the proximal N-terminal region in the inactivation of mammalian Kv1.4 channels, and suggest that the inactivation particle remains in close proximity to the permeation pathway even when the channel is in the open state.

Animals↗

PubMed1996

NIDDM is associated with loss of pancreatic beta-cell L-type Ca2+ channel activity.

Development of non-insulin-dependent diabetes mellitus (NIDDM) is associated with defects in glucose-stimulated insulin secretion. We have investigated Zucker diabetic fatty rats (ZDF), an animal model of NIDDM, and found that, compared with control islets, the expression of mRNA encoding C- and D-isoforms of alpha 1-subunits of beta-cell L-type voltage-dependent Ca2+ channels (VDCC) was significantly reduced in islets isolated from ZDF rats. This correlated with a substantial reduction of L-type Ca2+ currents (ICa) in ZDF beta-cells. Intracellular Ca2+ concentration responses in ZDF islets after glucose, KCI, or BAY K 8644 stimulation were markedly attenuated, whereas responses evoked by carbachol were unimpaired, consistent with a specific decrease in ICa in the diabetic islets. This reduction was accompanied by loss of pulsatile insulin secretion from ZDF islets treated with oscillatory increases of external glucose concentration. Our findings suggest that the attenuation of ICa in diabetic islets may contribute to the abnormal glucose-dependent insulin secretory responses associated with NIDDM and indicate that this defect is caused by decreased expression of genes encoding beta-cell VDCC alpha 1-subunits.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1996

K+ channels: generating excitement in pancreatic beta-cells.

K+ channels play a key role in cellular physiology by regulating the efflux of K+ ions. They are the most diverse group of ion channel proteins; more than 30 K+ channel genes have been characterized. Regulated by ATP, voltage, and calcium, multiple K+ channels coexist in the beta-cell to regulate membrane potential, cell excitability, and insulin secretion. Recent developments at the molecular level have greatly expanded our understanding of beta-cell K+ channel structure and function, especially in regard to the ATP-sensitive K+ channel, the target for sulfonylurea drugs. Mutations in K+ channel genes underlie diseases as diverse as persistent hyperinsulinemia of infancy, cardiac long QT syndrome, cerebellar degeneration, and certain ataxias. These discoveries have identified new pharmacological targets for possible therapeutic intervention in the treatment of diabetes.

ATP-Binding Cassette Transporters↗

PubMed1996

Isoform expression of the voltage-dependent calcium channel alpha 1E.

The alpha 1E voltage-dependent calcium channel has not been clearly identified with a specific neuronal calcium current. To help identify the role of alpha 1E, we examined differential expression of alpha 1E splice variants in mouse brain and cultured cell lines and examined the gene structure of the region encoding the amino terminal. Three splice variants were analyzed by a ribonuclease protection assay, and a fourth variant reported previously in a fetal human alpha 1E sequence was also detected in mouse brain and a pituitary cell line. Whole brain, telencephalon, and olfactory bulb contained predominantly the splice variant corresponding to alpha 1E-1 although other known variants could be detected. Neuroendocrine cells in vitro (beta TC3 insulinoma cells and AtT-20 pituitary cell lines) expressed predominantly one alpha 1E isoform. The existence of a 5' exon accounting for the origin of variant 5' ends reported in different species was suggested by the sequence of the mouse alpha 1E gene in the region encoding the amino terminal.

Alternative Splicing↗