Further Studies on 5‐hydroxytryptamine Transport in Pancreatic Islets and Isolated Β‐cells

Lindström, Per

doi:10.1111/j.1476-5381.1981.tb10433.x

Cited by 6 publications

(5 citation statements)

References 36 publications

(46 reference statements)

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“…Similarly, (+)-dihydrotetrabenazine, a substrate for the vesicular monoamine transporter 2 (VMAT2), has been explored for isletspecific imaging in vivo and drug delivery (Hao et al, 2016) However, VMAT2 expression may be insufficiently selective for b-cell-directed drug delivery (Eriksson et al, 2016). Likewise, the compound [ 11 C]5-hydroxytryptophan (HTP), which is selectively accumulated in the endocrine pancreas via the large amino acid transporter, was used to assess b-cell mass (Lindstro ¨m, 1981). However, rapid degradation of HTP-based probes by monoamine oxidase A may limit the feasibility of HTP-dependent islet targeting (Eriksson et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells

Horton

Allegretti

Lee

et al. 2019

Cell Chemical Biology

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Diabetes is a hyperglycemic condition characterized by pancreatic b-cell dysfunction and depletion. Whereas methods for monitoring b-cell function in vivo exist, methods to deliver therapeutics to b cells are lacking. We leveraged the rare ability of b cells to concentrate zinc to preferentially trap zinc-binding molecules within b cells, resulting in b-cell-targeted compound delivery. We determined that zinc-rich b cells and islets preferentially accumulated TSQ (6-methoxy-8-p-toluenesulfonamido-quinoline) in a zinc-dependent manner compared with exocrine pancreas. Next, we asked whether appending a zinc-chelating moiety onto a b-cell replicationinducing compound was sufficient to confer preferential b-cell accumulation and activity. Indeed, the hybrid compound preferentially accumulated within rodent and human islets in a zinc-dependent manner and increased the selectivity of replication-promoting activity toward b cells. These data resolve the fundamental question of whether intracellular accumulation of zinc-chelating compounds is influenced by zinc content. Furthermore, application of this principle yielded a proof-of-concept method for b-celltargeted drug delivery and bioactivity.

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Section: Introductionmentioning

confidence: 99%

Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells

Horton

Allegretti

Lee

et al. 2019

Cell Chemical Biology

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“…Externally added 5-HT is incorporated into the B cells of ob/ob mice [15][16][17][18]. The precursor, 5-HTP, is taken up and rapidly converted to 5-HT ]12-14].…”

Section: Discussionmentioning

confidence: 99%

“…Islet cells can accumulate and store 5-HT intracellularly [12][13][14] and the effects of elevation of intracellular 5-HT have been studied. Such elevation can be achieved in two ways; the B cells can take up and effectively decarboxylate the precursor, 5-hydroxytryptophan (5-HTP) [12][13][14] or they can accumulate exogenously added 5-HT [15][16][17][18]. The 5-HT accumulated is only slowly metabolized by the islets [14].…”

mentioning

confidence: 99%

Opposite effects of 5-hydroxytryptophan and 5-hydroxytryptamine on the function of microdissected ob/ob-mouse pancreatic islets

Lindström

Sehlin

1983

Diabetologia

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The effects of 5-hydroxytryptamine and 5-hydroxytryptophan on insulin release and 45Ca2+ uptake in islets microdissected from ob/ob mice were studied. At a concentration of 4 mmol/l both compounds slightly stimulated insulin release at a low glucose concentration (3 mmol/l). Insulin release induced by 20 mmol/l D-glucose was inhibited by 4 mmol/l 5-hydroxytryptamine but potentiated by 4 mmol/l L-5-hydroxytryptophan. Mannoheptulose (20 mmol/l) blocked the combined effects of 20 mmol/l D-glucose and 4 mmol/l L-5-hydroxytryptophan on insulin release. 45Ca2+ uptake was inhibited by 4 mmol/l 5-hydroxytryptamine and stimulated by 4 mmol/l L-5-hydroxytryptophan. Mannoheptulose (20 mmol/l) did not affect the 45Ca2+ uptake induced by the latter. When 4 mmol/l L-5-hydroxytryptophan was present only during the 30-min preincubation period. 20 mmol/l-glucose-induced insulin release and 45Ca2+ uptake during a subsequent incubation period were inhibited. Externally added 5-hydroxytryptamine (4 mmol/l) did not change the effects of 4 mmol/l L-5-hydroxytryptophan on insulin release and 45Ca2+ uptake. It is concluded that, when added directly into the incubation medium, 5-hydroxytryptophan has effects on insulin release and 45Ca2+ uptake which are opposite to those observed when 5-hydroxytryptamine is added. These effects do not seem to be mediated by 5-hydroxytryptamine formed intracellularly from 5-hydroxytryptophan.

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“…The transport process operative under these conditions appeared to be principally one of diffusion. Studies with mouse islet cells (Lindstrom, 1981) have indicated that at submicromolar 5-hydroxytryptamine concentrations there is a second Na+-dependent 5-hydroxytryptamine uptake process that may correspond to the high-affinity uptake system that is present in brain tissue (Ross & Renyi, 1967). There was no evidence of this, however, in our experiments.…”

Section: Cellular Uptake Studiesmentioning

confidence: 99%

“…Investigation of the net uptake of 5-hydroxytryptamine radioactivity by intact islets and by dispersed islet cells from ob/ob mice has suggested the functioning in the B-cell of a high-affinity Na+-dependent 5-hydroxytryptamine transport system of low capacity together with a low-affinity non-saturable transport process (Lindstrom et al, 1980;Lindstrom, 1981). Considerable variation is evident in the uptake rates in different species (Mahoney & Feldman, 1977).…”

mentioning

confidence: 99%

5-Hydroxytryptamine transport in cells and secretory granules from a transplantable rat insulinoma

Hutton¹,

Peshavaria²,

Tooke³

1983

Biochemical Journal

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Mechanisms of transport of 5-hydroxytryptamine in the pancreatic B-cell were investigated by using cell suspensions and secretory granules prepared from a transplantable rat insulinoma. (1) Cells incubated with 5-hydroxy[G-3H]tryptamine at concentrations ranging from 0.1 microM to 5 mM accumulated the radioisotope principally by a simple diffusion process. The incorporated radioactivity was recovered principally as the parent molecule and was recovered predominantly in soluble protein and secretory-granule fractions prepared from the tissue. (2) Isolated granules incubated in buffered iso-osmotic medium without ATP accumulated the amine to concentrations up to 38-fold that of the medium. This process was insensitive to reserpine and occurred over a wide range of 5-hydroxytryptamine concentrations (0.075 microM-25 mM). Above 5 mM, 5-hydroxytryptamine accumulation decreased in parallel with the breakdown of the delta pH across the granule membrane. Uptake was favoured by alkaline media and was reduced by the addition of (NH4)2SO4. In both cases a close correlation was observed between uptake and the transmembrane delta pH, a finding that suggested that 5-hydroxytryptamine permeated the membrane as the free base and equilibrated across the membrane with the delta pH. Binding of 5-hydroxytryptamine to granule constituents also played a part in this process. ATP caused a further doubling of granule 5-hydroxytryptamine uptake by a process that was sensitive to reserpine (0.5 microM). Inhibitor studies suggested that amine transport in this instance was linked to the activity of the granule membrane proton-translocating ATPase. (3) It was concluded that the uptake of amines driven by proton gradients across the insulin-granule membrane could account for the accumulation in vivo of amines in the B-cell.

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Further Studies on 5‐hydroxytryptamine Transport in Pancreatic Islets and Isolated Β‐cells

Cited by 6 publications

References 36 publications

Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells

Zinc-Chelating Small Molecules Preferentially Accumulate and Function within Pancreatic β Cells

Opposite effects of 5-hydroxytryptophan and 5-hydroxytryptamine on the function of microdissected ob/ob-mouse pancreatic islets

5-Hydroxytryptamine transport in cells and secretory granules from a transplantable rat insulinoma

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