Regulation of Voltage-Sensitive Calcium Channels in Brain by Micromolar Affinity Benzodiazepine Receptors

DeLorenzo, Robert J.; Taft, William C.; Andrews, Wendy

doi:10.1007/978-1-4613-2307-5_24

Cited by 1 publication

(3 citation statements)

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“…A Scatchard plot of the saturation data indicated a KD of 28.6 p M and a TB of 199.4 pmollmg of protein. These values are consistent with the KD and TB values reported for low affinity benzodiazepine receptors in other peripheral tissues and brain (Bowling and DeLorenzo, 1982;DeLorenzo, Taft, and Andrews, 1986).…”

Section: Induction Of Hl-60 Differentiation By Benzodiazepinessupporting

confidence: 91%

“…The present report describes the presence of benzodiazepine receptors with micromolar affinity constants in membrane fractions from HL-60 cells. Recent evidence suggests that low affinity benzodiazepine receptors may represent binding to multiple subclasses of receptors with affinities ranging from 500 nM to 200 pM (DeLorenzo, Taft, and Andrews, 1986). The existence of multiple subclasses of low affinity benzodiazepine receptors in HL-60 membranes has not been investigated, but must be considered in identifying the molecular interactions mediating benzodiazepine-induced differentiation in this cell line.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the observation that some of the pharmacological activities of the benzodiazepines do not correlate with their avidity toward central or peripheral high affinity binding sites has led to the discovery of a distinct class of lower affinity receptors which bind benzodiazepines in the micromolar concentration range (Bowling and DeLorenzo, 1982). Lower affinity benzodiazepine binding sites are found in both brain and peripheral tissue (DeLorenzo, Taft, and Andrews, 1986) and can be distinguished from high affinity benzodiazepine receptors by several pharmacological criteria (Bowling and DeLorenzo, 1982). The physiological function of high affinity and low affinity peripheral benzodiazepine receptors is unknown, although a possible involvement in the inhibition of cell proliferation has been suggested (Wang, Morgan, and Spector, 1984b).…”

mentioning

confidence: 99%

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The role of benzodiazepine receptors in the induction of differentiation of HL‐60 leukemia cells by benzodiazepines and purines

Ishiguro

Taft

DeLorenzo

et al. 1987

Journal Cellular Physiology

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A series of benzodiazepines was evaluated for their capacity to induce the differentiation of HL-60 acute promyelocytic leukemia cells. Benzodiazepines were effective initiators of maturation in the concentration range of 50 to 150 microM. The possible involvement of benzodiazepine receptors in mediating the differentiation induced by these agents was investigated. The presence of high affinity, peripheral type benzodiazepine binding sites (KD = 7.3 nM, TB = 14.5 pmol/mg protein with Ro5-4864) was demonstrated in HL-60 membranes. The occupancy of peripheral type high affinity benzodiazepine receptors by various benzodiazepines showed some correlation (r = 0.76) with their differentiation-inducing capabilities, but binding potencies were 1,000-fold higher than the concentrations required to produce differentiation. A class of benzodiazepine receptors with lower binding affinity was also detected in HL-60 membranes (KD = 28.6 microM; TB = 199 pmol/mg protein with diazepam). A higher level of correlation (r = 0.88) was demonstrated between benzodiazepine occupancy of these lower affinity receptors and the capacity to induce maturation. Significantly, benzodiazepine concentrations needed for low affinity binding and induction of differentiation were the same (25-200 microM), suggesting that low affinity benzodiazepine receptors may be involved in the induction process. We have shown that the molecular form responsible for the induction of the differentiation of HL-60 cells to mature forms by 6-thioguanine (TGua) is the free base, TGua, itself [Ishiguro, Schwartz, and Sartorelli (1984) J. Cell. Physiol., 121:383-390]. Since hypoxanthine (Hyp) and inosine (Ino) have been identified as putative endogenous ligands for high affinity benzodiazepine receptors in brain tissue, the potential involvement of benzodiazepine receptors in the differentiation of HL-60 cells by the purines was investigated. Physiological purines such as Hyp and Ino were inactive in displacing the benzodiazepines from their high and low affinity binding sites in HL-60 membranes. In contrast, TGua caused inhibition of benzodiazepine binding to high and low affinity sites. The inhibition of Ro5-4864 binding to high affinity binding sites by TGua appeared to be due to the binding of TGua to membranes through the formation of a mixed disulfide between the 6-thiopurine and protein thiols, since the inhibition was reversed by the presence of 2-mercaptoethanol. The findings suggest a possible relationship between the occupancy of benzodiazepine receptors by TGua and the induction of leukemic cell differentiation.

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Section: Induction Of Hl-60 Differentiation By Benzodiazepinessupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%