Histamine uptake into non-neuronal brain cells

Abstract

IntroductionThe main function of various transport systems is to maintain the cellular concentrations of the physiological substances. However, transport also contributes to various mechanisms in clearing and scavenging substances from the interstitial spaces. In the CNS, the termination of many neurotransmitters involves rapid removal from the synapse; mainly by uptake either into presynaptic terminal or into the surrounding glia through specialised transport systems.Histamine (HA) is a regulator of the vascular permeability through cerebrovascular endothelium as well as being a central neurotransmitter. However, no neuronal uptake of HA has been detected in vertebrates [1]. In invertebrates, HA is taken up into the photoreceptor terminals and surrounding glia and replenishes HA stores by an activitydependent fashion [2]. In mammalian neurones, a polyspecific cation transporter (hOCT 2 ) can transport HA along with monoamines [3] but as it shows a low affinity for HA (K M in mM range), it is not assumed to play a considerable role in HA inactivation.Besides inactivation, the possibility of a clearance mechanism in which glial and cerebral endothelial HA uptake are co-operatively involved, has also been considered. We have focused our research on HA uptake by CNS-resident nonneuronal cells (including mast cells) bearing physiological significance. Histamine uptake by astroglial cellsAstrocytes perform a variety of CNS functions, including uptake of a number of neurotransmitters. In 1985, we showed that HA is taken up and slowly metabolised by chick astroglial cells [4]. In chick astroglial cells (grown as monolayer culture), uptake was found to be saturable, with high affinity for HA and relatively low capacity (K M = 0.24 mM; V max = 0.31 pmol/mg protein/min), showing energy-requirements and strong sensitivity to extracellular Na + concentration. The uptake vs [Na + ] curve was saturable, fitted the Michaelis-Menten equation and resulted in a K M of 172 mM for Na + . HA taken up into these cells was slowly metabolised and/or released ('reversed uptake'), dependent on the shift of the Na + /K + gradient [5].Bidirectonal uptake could also be detected in astroglial cultures from postnatal (P 0 -P 6 ) rat brains with similar affinity for HA (K M = 0.19 mM) but with 10 times higher capacity (V max = 3.12 pmol/mg protein/min) [6]. It was noteworthy that partial dissipations of the inward oriented Na + (in < out) and the outward oriented K + (in > out) gradient could reverse the inward-directed HA uptake resulting in a carrier-mediated release of HA. The release of HA was increased by high [K + ] and K + channel blockers which might depolarise the cells, suggesting an electrogenic transporter for the uptake. The HA analogues, 2-meHA and 4-me-HA showed significant inhibition while well-known uptake inhibitors (imipramine and cocaine) did not show much effect on the uptake [6]. Impromidine and the impromidine derivative, VUF 8407 [9] showed potent inhibitory effects on HA uptake and antagonistic actions on the H 3 auto-r...

Molecular mechanism of histamine clearance by primary human astrocytes

“…Rat astrocytes were capable of significant histamine uptake, but rat synaptosomes did not have histamine transport activity. In addition to these in vitro experiments, Huszti et al demonstrated that astrocytes played a crucial role in the clearance of brain histamine in vivo (Huszti, 1998(Huszti, , 2003Huszti et al, 1998). In addition to these in vitro experiments, Huszti et al demonstrated that astrocytes played a crucial role in the clearance of brain histamine in vivo (Huszti, 1998(Huszti, , 2003Huszti et al, 1998).…”

Histamine (re)uptake by astrocytes: an experimental and computational study

“…Among glial cells astrocytes have been proposed to be the main histamine inactivation site [6]. Reports from Huszti´s laboratory described bidirectional [7][8][9] histamine uptake into cultured glial cells prepared from embryonic chicks [7] and neonatal rats [8][9][10] which was Na + -but not Cl --dependent [11]. Glial cells were also found to be involved in the continuous removal of neuronal histamine from the synaptic cleft in in vivo conditions [12].…”

Kinetic and pharmacological properties of [3H]-histamine transport into cultured type 1 astrocytes from neonatal rats

“…Reports from Huszti's laboratory described histamine uptake by cultured glial cells prepared from embryonic chicks [10] and neonatal rats [11][12][13], which was Na + -dependent [14] and bidirectional [10,12]. In order to demonstrate histamine uptake into cultured glial cells, astrocytes from neonatal (P0-P6) rats required maintenance in culture for at least 19 days [11,14].…”