Differential ontogeny of alpha 1-adrenergic and cholinergic receptor sites in the atria and ventricles of the inbred Dahl hypertension-sensitive (S/JR) and -resistant (R/JR) rat

The ontogeny of atrial and ventricular alpha 1-adrenergic and muscarinic cholinergic receptor sites was investigated in inbred Dahl hypertension-sensitive (S/JR) and -resistant (R/JR) rats between 5 and 150 days of age. The density of sites in both cardiac regions was generally greater in the neonate than mature rat. A marked proliferation of sites was observed in neonatal and young adult rats that occurred in the following order: ventricular cholinoceptors----ventricular adrenoceptors----atrial cholinoceptors----atrial adrenoceptors. The density of ventricular adrenoceptors was greater in the S/JR rat than the R/JR rat at 5 days of age. At 150 days of age, the density of sites was less in the S/JR rat than the age-matched R/JR rat or the normotensive 50-day-old S/JR rat. The development of atrial adrenoceptors was similar between the strains, regardless of the blood pressure. The density of ventricular cholinergic receptors was greater in the S/JR strain at 5 and 15 days of age. However, the density of atrial cholinergic sites was consistently greater in the S/JR strain throughout development. The results of this study suggest that: (1) significant prenatal receptor development occurs in the heart; (2) receptor development may precede the functional maturation of postganglionic autonomic efferents; and (3) distinguishing differences in the regional density of alpha 1-adrenergic and muscarinic cholinergic binding sites are present between S/JR and R/JR rats at much earlier points in development than previously shown.     

DL-sodium lactate reduces alpha 1-adrenergic receptor binding in rat and mouse brain

DL-Sodium lactate decreases the density of alpha 1-adrenergic receptors in rat brain membranes in vitro, an effect that is not present for several other neuroreceptors under similar conditions. Moreover, similar effects on specific 3H-prazosin binding to alpha 1-adrenergic receptors can be seen in the mouse brain after intravenous (i.v.) administration of DL-sodium lactate. Since these effects can be observed with i.v. doses of DL-sodium lactate only slightly higher than the doses needed to provoke panic attacks in susceptible patients, it seems possible that similar changes in central neurotransmission might be involved in the biological mechanism underlying the induction of panic attacks by DL-sodium lactate.     

alpha1-adrenergic receptor-induced slow rhythmicity in nonrespiratory cervical motoneurons of neonatal rat spinal cord

Previous studies have reported that the alpha1-adrenergic system can activate spinal rhythm generators belonging to the central respiratory network. In order to analyse alpha1-adrenergic effects on both cranial and spinal motoneuronal activity, phenylephrine (1-800 microM) was applied to in vitro preparations of neonatal rat brainstem-spinal cord. High concentration of phenylephrine superfusion exerted multiple effects on spinal cervical outputs (C2-C6), consisting of a lengthening of respiratory period and an increase in inspiratory burst duration. Furthermore, in 55% of cases a slow motor rhythm recorded from the same spinal outputs was superimposed on the inspiratory activity. However, this phenylephrine-induced slow motor rhythm generated at the spinal level was observed neither in inspiratory cranial nerves (glossopharyngeal, vagal and hypoglossal outputs) nor in phrenic nerves. Whole-cell patch-clamp recordings were carried out on cervical motoneurons (C4-C5), to determine first which motoneurons were involved in this slow rhythm, and secondly the cellular events underlying direct phenylephrine effects on motoneurons. In all types of motoneurons (inspiratory and nonrespiratory) phenylephrine induced a prolonged depolarization with an increase in neuronal excitability. However, only nonrespiratory motoneurons showed additional rhythmic membrane depolarizations (with spiking) occurring in phase with the slow motor rhythm recorded from the ventral root. Furthermore the tonic depolarization produced in all motoneurons results from an inward current [which persists in the presence of tetrodotoxin (TTX)] associated with a decrease in neuron input conductance, with a reversal potential varying as a Nernstian function of extracellular K+ concentration. Our results indicate that the alpha1-adrenoceptor activation: (i) affects both the central respiratory command (i.e. respiratory period and inspiratory burst duration) and spinal inspiratory outputs; (ii) induces slow spinal motor rhythmicity, which is unlikely to be related to the respiratory system; and (iii), increases motoneuronal excitability, probably through a decrease in postsynaptic leak K+ conductance.     

Properties and regional distribution of nicotinic cholinergic receptors in the rat hypothalamus

The rat hypothalamus has the capacity to bind α-bungarotoxin with high affinity to a saturable number of non-interacting receptors with a pharmacologic profile consistent with a nicotinic receptor. Studies of the hypothalamic nuclear distribution of cholinergic receptors showed no specific pattern of enrichment of muscarinic receptors. In contrast, there was a distinct distribution of nicotinic receptors with high concentrations in the suprachiasmatic, dorsomedial and preoptic suprachiasmatic nuclei. Thus, the quantitative distribution of nicotinic receptors in hypothalamic nuclei is in general agreement with the observed autoradiographic distribution of radioactive alpha bungarotoxin. Further, these results confirm the existence of high concentrations of nicotinic receptors in hypothalamic regions of the rat implicated in neuroendocrine function.     

Distribution of alpha 2-adrenergic receptor mRNAs in the rat CNS.

alpha 2-Adrenergic receptors (ARs) are involved in central nervous system (CNS) control of blood pressure. It is now known that there are three human genes that encode subtypes of alpha 2-ARs, but little is known regarding the distribution of these subtypes throughout the CNS. The availability of receptor clones allows the mapping of mRNAs encoding the individual alpha 2-AR subtypes in the CNS. In this communication, we report that there are three, closely related rat alpha 2-AR genes. We have developed subtype-specific hybridization probes from each of these genes and have used these reagents to measure alpha 2-AR subtype mRNA accumulation in extracts of discrete regions of the rat CNS. We found that mRNAs encoding the alpha 2A-AR and alpha 2C-AR subtypes are distributed widely, but unevenly, throughout the rat CNS. The A subtype is prominent in the midbrain, brainstem, spinal cord, pituitary and diencephalon while the C subtype predominates in basal ganglia and cerebellum. The cortex, olfactory bulb and hippocampus contain roughly equal amounts of the alpha 2A- and alpha 2C-AR mRNAs. A third subtype's (alpha 2B-AR) mRNA is far less abundant in brain tissues, and is only found in the diencephalon.     

Development of adrenergic receptor binding sites in brain regions of the neonatal rat: effects of prenatal or postnatal exposure to methylmercury

In order to understand the effects of developmental exposure to methylmercury on the ontogeny of synaptic function, we examined the impact of prenatal or postnatal exposure on acquisition of receptor binding sites for norepinephrine. The actions of the mercurial were both regionally- and receptor subtype-selective and depended upon the maturational profile of each region. alpha 1- alpha 2- and beta-receptor sites in the cerebellum, the region which develops last, were the most vulnerable to methylmercury. In contrast, the same receptor subtypes in the midbrain + brainstem, which develops earliest, were resistant to methylmercury. The cerebral cortex, which matures at a time midway between cerebellum and midbrain + brainstem, also displayed intermediate vulnerability to actions of methylmercury on receptors. Within the cerebellum, prenatal exposure to 1 mg/kg of methylmercury interfered the most with ontogeny of alpha 1-receptor binding, less so for alpha 2-receptors and least for beta-receptors. Lower doses of methylmercury tended to increase receptor binding for all subtypes, a fact which may contribute to promotion of neurological development seen in animals exposed to those levels. These data support the view that methylmercury exerts a dual spectrum of action on developing synapses, with promotional effects predominating at low doses and inhibitory actions at higher doses. The net effect on responsiveness to neurotransmitters is influenced, in part, by the actions on developing receptor sites which are in turn dependent upon the specific regional timetables for cellular maturation and receptor acquisition.     

Effects of neonatal methylmercury exposure on development of nucleic acids and proteins in rat brain: regional specificity

Exposure of neonatal rats to methylmercury (1 or 2.5 mg/kg SC daily) during the preweaning period caused regionally-specific alterations in DNA, RNA and protein content in brain. In midbrain + brainstem, where neuronal replication and differentiation conclude early, reduced DNA content was prominent at either dose and was apparent well before evidence of general body growth impairment; small deficits in protein content and brain region weight were seen. In contrast, cerebral cortex showed an elevation of DNA in the high dose group and a tendency toward supranormal RNA values at either dose. In cerebellum, where maturation occurs last, both DNA and RNA were markedly stimulated in pups receiving either 1 or 2.5 mg/kg and little effect was seen on proteins or region weight. These results indicate that the response of the developing central nervous system to cell loss caused by methylmercury is dependent upon the stage of development at which exposure occurs: whereas clear-cut reductions in cell number (DNA content) occur in fairly mature, post-replicative regions, those areas undergoing rapid replication and differentiation are likely to exhibit compensatory stimulation or replacement of cells.     

Characterization and regional distribution of glutamatergic and cholinergic ligand binding sites in goldfish brain

The binding of several ligands that selectively interact with glutamate receptor subtypes was characterized in extensively washed synaptosomal membrane preparations from goldfish brain. The binding affinity (Kd), an estimate of the number of sites (Bmax), the rank-order potency of glutamatergic ligands at inhibiting binding, and the regional localization of binding sites were determined. In whole brain preparations, 3H-kainate had a Kd of 136 nM and a Bmax of 63 pmol/mg protein, 3H-AMPA had a Kd of 26 nM and a Bmax of 0.4 pmol/mg protein, and 3H-L-glutamate bound with an apparent affinity of 323 nM and a Bmax of 5 pmol/mg protein. Most of the binding sites for each of the glutamate analogs were present in the cortex and the fewest were in the cerebellum, except for 3H-kainate binding sites, which were most prevalent in the cerebellum and least abundant in the cortex. The proposed neuronal nicotinic acetylcholine receptor (nAChR) ligands 3H-(-)nicotine and 125I-alpha-Bgt were also investigated. 125I-alpha-Bgt had a Kd of 0.08 nM and a Bmax of 132 fmol/mg protein. 3H-(-)nicotine did not bind to the extensively washed membrane preparations, so a less stringently washed P2 tissue fraction was used. In this tissue preparation, 3H-(-)nicotine had a Kd of 9 nM and a Bmax of 84 fmol/mg protein. Eye removal resulted in a time-dependent decrease in the number of 3H-(-)nicotine and 125I-alpha-Bgt binding sites in the contralateral optic tectum, but no reduction in the number of binding sites for any of the glutamatergic ligands. The results suggest that both 3H-(-)nicotine and 125I-alpha-Bgt binding sites are similarly regulated in the optic tectum, which supports previously reported data indicating that the binding sites are located on closely related proteins or may, at least partially, be colocalized on the same protein (Henley and Oswald, 1987).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pre- and postsynaptic alterations in the septohippocampal cholinergic innervations after prenatal exposure to drugs

The present study was designed to evaluate possible presynaptic and postsynaptic alterations in the hippocampal cholinergic innervations that account for the hippocampus-related behavioral deficits found after prenatal drug exposure. Mice were prenatally exposed to either phenobarbital or heroin. On postnatal day 50, the hippocampi were removed and protein kinase C (PkC) activity, the amounts of Gi, Go, and Gq guanosine 5’-triphosphate binding proteins (G-proteins), and choline transports were determined. Basal PkC activity was higher than control levels in both phenobarbital and heroin treated mice, by 41% and 35%, respectively. The increase of PkC activity in response to carbachol was impaired in both treatment groups: in control mice, membrane PkC activity in hippocampal slices increased by 40%–50%, while no such response, or even slight reduction in PkC activity, was observed in the drug-exposed offspring. A significant increase was found in Gi and Gq G-proteins (18%–21%) in mice exposed to phenobarbital or to heroin compared with control levels. The amount of choline transporters, determined by hemicholinium binding, increased by 70% compared with the control level in mice prenatally exposed to heroin, and increased by 71% in mice prenatally exposed to phenobarbital. The alterations in basal and carbachol-stimulated hippocampal PkC activity after prenatal drug exposure may be related to an impairment in long-term potentiation (LTP); which plays an important role in hippocampal related behavioral abilities, changes in which are caused by prenatal drug exposure.     

Developmentally different onset of alpha 1- and alpha 2-adrenergic responses in the neonatal rat dorsal motor nucleus of the vagus in vitro

Development of noradrenergic responses in the rat dorsal motor nucleus of the vagus (DMV) from postnatal days 0 to 22 was studied by a conventional microelectrode technique using brain slice preparations. Between postnatal days 0 and 6, noradrenaline (NA) caused only alpha 1-adrenoceptor-mediated depolarizations. By postnatal day 14, alpha 2-adrenoceptor-mediated hyperpolarization appeared. During the next postnatal week, the response pattern to NA became similar to that in adults, including both alpha 1- and alpha 2-adrenergic responses. These results suggest that alpha 2-adrenergic responses in DMV neurons are absent at birth but develop rapidly in the 3 weeks after birth. Furthermore, alpha 1-adrenoceptors have already been functioning in the fetal period.     

Development of the alpha7 nicotinic cholinergic receptor in rat hippocampal formation

The alpha7 nicotinic receptor has been implicated in the regulation of a variety of developmental processes. The goal of the present study was to assess whether the alpha7 receptor might participate in the regulation of hippocampal ontogeny by describing the spatiotemporal development of alpha7 mRNA and alpha-bungarotoxin binding in rat hippocampal formation. Message for the alpha7 receptor was initially observed in the hippocampal neuroepithelium at embryonic day 13 and in the anlage of the hippocampal formation on embryonic day 14. Binding of alpha-bungarotoxin was initially seen on embryonic day 15 in the dorsal portion of the anlage of stratum oriens and stratum radiatum-lacunosum moleculare, but was never observed in the neuroepithelium. Dramatic elevations in both alpha7 mRNA and alpha-bungarotoxin binding were observed in most regions of the hippocampal formation neonatally. The levels of both alpha7 message and protein gradually decreased during the first three postnatal weeks to adult levels in most regions. The lack of alpha-bungarotoxin binding in the neuroepithelium suggests that the alpha7 receptor does not influence neurogenesis. The early appearance and complex, prolonged pattern of development of the alpha7 receptor suggest that it may influence processes as diverse as cell migration, dendritic elaboration and apoptosis during hippocampal maturation.     

Muscarinic cholinergic receptor M1 in the rat basolateral amygdala: Ultrastructural localization and synaptic relationships to cholinergic axons

Muscarinic neurotransmission in the anterior basolateral amygdalar nucleus (BLa) mediated by the M1 receptor (M1R) is critical for memory consolidation. Although knowledge of the subcellular localization of M1R in the BLa would contribute to an understanding of cholinergic mechanisms involved in mnemonic function, there have been no ultrastructural studies of this receptor in the BLa. In the present investigation, immunocytochemistry at the electron microscopic level was used to determine which structures in the BLa express M1R. The innervation of these structures by cholinergic axons expressing the vesicular acetylcholine transporter (VAChT) was also studied. All perikarya of pyramidal neurons were labeled, and about 90% of dendritic shafts and 60% of dendritic spines were M1R+. Some dendrites had spines suggesting that they belonged to pyramidal cells, whereas others had morphological features typical of interneurons. M1R immunoreactivity (M1R‐ir) was also seen in axon terminals, most of which formed asymmetrical synapses. The main targets of M1R+ terminals forming asymmetrical synapses were dendritic spines, most of which were M1R+. The main targets of M1R+ terminals forming symmetrical synapses were M1R+ perikarya and dendritic shafts. About three‐quarters of VAChT+ cholinergic terminals formed synapses; the main postsynaptic targets were M1R+ dendritic shafts and spines. In some cases M1R‐ir was seen near the postsynaptic membrane of these processes, but in other cases it was found outside of the active zone of VAChT+ synapses. These findings suggest that M1R mechanisms in the BLa are complex, involving postsynaptic effects as well as regulating release of neurotransmitters from presynaptic terminals. J. Comp. Neurol. 521:1743–1759, 2013. © 2012 Wiley Periodicals, Inc.     

Muscarinic cholinergic receptor regulation and acetylcholinesterase inhibition in response to insecticide exposure during development

Neonatal rats were exposed to parathion, an acetylcholinesterase inhibiting organophosphorus pesticide, during a rapid phase of cholinergic receptor development. Rats were given subcutaneous injections of 1.5 mg/kg/day from postnatal days 8–20. The immediate effects of subchronic developmental exposure were assessed in 21-day-old animals and more persistent effects assessed in 36-day-old animals. There was a 61% inhibition of acetylcholinesterase and a 27% decrease of muscarinic receptor density in 21-day-old treated rats. The reduction in receptor density was dose-dependent and a significant correlation was found between the level of acetylcholinesterase inhibition produced by parathion and the reduction in receptor density. It was estimated that a minimum of at least 15% prolonged inhibition of forebrain acetylcholinesterase by parathion was necessary to reduce receptor density. Regional analyses of receptor autoradiograms of 21-day-old animals indicated muscarinic receptors in the cortex and hippocampus were preferentially lost. The anterior thalamus was notable in having a high density of cholinergic receptors which were unaffected by parathion treatment. No changes were found in the affinity of [³H]QNB for the receptor or in the binding of the agonist, acetylcholine, in competition binding studies. AChE activity and muscarinic receptor density returned to normal after a 16 day recovery period. Parathion treated animals were growth inhibited but, growth retardation induced by undernutrition did not alter receptor density or affinity of QNB for muscarinic receptors. Thus, the transient decrease in receptor density in parathion exposed animals was similar to the response previously observed in adults and was not secondary to growth retardation or undernutrition. Receptor densities and acetylcholinesterase levels were regulated back to normal values after a 16 day recovery period in spite of the perturbation of cholinergic function during cholinergic synapse and receptor development.     

Serum protein leakage in aged human brain and inhibition of ligand binding at alpha 2-adrenergic and cholinergic binding sites

Serum proteins are known to extravasate into the brain parenchyma in senile and presenile dementia (Glenner: Hum. Pathol. 16:433-435, 1986; Wisniewski and Kozlowski: Ann. NY Acad. Sci. 396:119-129, 1982). We have recently demonstrated that human serum Cohn fraction IV (alpha-globulin enriched) inhibits ligand binding at putative dopamine and serotonin2 receptors labeled by [3H]spiroperidol in human brain (Andorn, Pappolla, Fox, Klemens, and Martello: Proc. Natl. Acad. Sci. USA 83:4572-4575, 1986). We now demonstrate that serum proteins can be identified in the neuropil and in neuronal cell bodies in normal aged brain, that alpha-globulin-enriched fractions inhibit ligand binding at alpha 2-adrenergic and muscarinic binding sites in human brain as well, and that serum proteins can be identified within neuronal cytoplasm and axons.     

Pre- and postnatal development of opiate receptor subtypes in rat spinal cord

We have studied the developmental expression of opiate binding sites in the rat spinal cord at various prenatal and postnatal stages. For each developmental stage, we have compared the expression pattern of kappa receptors with that of mu and delta receptor subtypes. Both mu and kappa receptors appear relatively early during spinal cord ontogeny (from the 15th prenatal day), while delta sites are expressed later at the postnatal period (starting at the 1st postnatal day). The number of kappa sites predominates throughout the development (55-80% of total opiate sites) with two peaks of binding activity: one at the 20th gestational day, and the other around the 7th postnatal day. mu sites represent 20-38% of the total opiate receptor population with one peak of binding activity appearing at the 1st postnatal day. The densities of mu and kappa receptors at the adult stage are lower by 40-50% than the peak values observed at the early postnatal periods. The relative amounts of delta sites remain low throughout the ontogeny (4-8% of the total opiate sites). The binding properties of neonatal (1 day after birth) kappa sites (ligand binding affinities, regulation of agonist binding by guanosine triphosphate and various cations) are similar to those displayed by kappa receptors in adult spinal cord.     

Alpha 1- and alpha 2-adrenoceptor binding in the Dahl rat model of hypertension

Dahl sensitive rats on a high salt diet (DSH group) developed significant elevations in blood pressure (BP). Sensitive rats maintained on a low salt diet (DSL group) and Dahl resistant rats on a high or low salt diet (DRH and DRL groups, respectively) remained normotensive. The DSH and DRH groups displayed a lower density of alpha 2-adrenoceptors (as measured with [3H]-clonidine) in the cerebral cortex than normotensive DSL and DRL groups. In contrast, the density of alpha 2-adrenoceptors in the medulla was significantly lower in the DSH group than the DSL group, but significantly higher in the DRH group compared to the DRL group. The density of alpha 1-adrenoceptors (as measured with [3H]-WB4101) in the hypothalamus was lower in the DSH group than the DSL group but greater in the DRH group than the DRL group. The results suggest that the sensitive and resistant lines can be distinguished by the density of alpha 1- adrenoceptors in the hypothalamus and medulla, respectively. The interactive effects of dietary NaCl and susceptibility to hypertension on adrenoceptors lend further support to the hypothesis that the genetic predisposition to hypertension is associated with a disruption in central adrenergic activity.     

Postnatal development of the alpha1 containing GABAA receptor subunit in rat hippocampus

Here we have studied the developmental expression of alpha1 subunit of the GABAA receptor in comparison with the expression of alpha2 subunit and several GABAergic markers (parvalbumin (PV), calretinin (CR), somatostatin (SOM), neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP)). The alpha1 expression (mRNA and protein) was low at birth and increased progressively until the adulthood. This expression pattern was similar to that observed for PV, opposite to that of CR (high at birth and decreased continuously until the adulthood) and differed from that observed for the alpha2 and neuropeptides (SOM, NPY and VIP) (in all cases, a clear peak in expression was observed at P10). We further investigated the expression of alpha1, PV and CR by immunohistochemistry. As expected, the alpha1 and the PV expression were low at birth and increased progressively until the adulthood. Both alpha1 and PV were co-expressed by the same interneuronal population, however, the maturation of the alpha1 subunit preceded to that of PV. Finally, we observed a gradient of maturation between the different fields of the hippocampus proper (CA2-3 preceded to CA1 and DG). This gradient could be related to the high expression of CR positive cells and fibers during the first 10 postnatal days, located principally in the stratum lacunosum moleculare of the CA2-3 layers.     

Influence of prenatal ethanol exposure on cholinergic development in the rat striatum

This study investigated the influence of ethanol exposure throughout gestation on cholinergic development within the rat striatal region. Pregnant Long-Evans rats were maintained on three diets throughout gestation: A liquid diet in which ethanol accounted for 35–39% of the total calories, a similar diet with the isocaloric substitution of sucrose for ethanol, and a lab chow control diet. At postnatal days 14 and 60 (P14 and P60), the striatal regions of the offspring were analyzed for the number of cholinergic neurons, via choline acetyltransferase (ChAT) immunostaining. The area of the striatum was also measured in these animals. At P14, P21, and P60, ChAT activity was assessed in the same region. These analyses revealed a significant increase in the number of cholinergic striatal neurons at P14 in the animals which had been exposed prenatally to ethanol. This increase was transient, however, with equal numbers of ChAT-positive cells found in all three groups by adulthood (P60). The brain weights of the ethanol-exposed animals were significantly reduced at P14 and P21, but were comparable to controls by P60. There were no significant differences in the striatal area or the overall volume of the region assessed, however, at either P14 or P60. Although there were some increases in ChAT activity across the ages viewed (most notably between P14 and P21), there were no effects of diet on ChAT activity at any age assessed. It is proposed that the increased numbers of cholinergic neurons could be a function of errors in migration, enhanced neurogenesis, diminished cell death, alterations in gene expression, or increased cell survival as a result of alterations in neurotrophic factor production or availability. © 1996 Wiley-Liss, Inc.     

Astroglial cells in vitro are heterogeneous with respect to expression of the alpha 1-adrenergic receptor

A wide variety of approaches have been used to examine the expression of neuroligand receptors by cultured astroglial cells. The results of such studies make it clear that these cells exhibit most, if not all, of the different receptors known to be associated with central neurons. However, it has been more difficult to determine if there are multiple populations of astroglia that can be distinguished on the basis of their complement of neuroligand receptors. To address this question, we established a radioligand binding assay that enabled us to visualize alpha 1-adrenergic receptors (alpha 1-ARs) on immunocytochemically defined neural cells. Saturation, time course, and competition binding experiments determined that 125I-HEAT could be used to identify alpha 1-AR binding sites on immunocytochemically defined astroglial cells. Our results indicate that approximately 66% of cortical polygonal astroglia express detectable numbers of alpha 1-ARs. 3H-thymidine labeling experiments indicate that both dividing and nondividing astroglia exhibit alpha 1-ARs. These results greatly contrast with studies on beta-adrenergic receptor expression (beta-AR), in which 100% of polygonal astroglia express beta-ARs. Process-bearing astroglia also exhibit alpha 1-ARs, which is in marked contrast to the lack of beta-AR expression by these cells. The results presented here suggest that astroglia, like neurons, differ in the receptors they express and therefore may be able to selectively respond to extracellular stimulation.