Axonal transport of muscarinic cholinergic receptors in rat vagus nerve: high and low affinity agonist receptors move in opposite directions and differ in nucleotide sensitivity

Abstract

The presence and transport of muscarinic cholinergic binding sites have been detected in the rat vagus nerve. These binding sites accumulate both proximal and distal to ligatures in a time-dependent manner. The results of double ligature and colchicine experiments are compatible with the notion that the anterogradely transported binding sites move by fast transport. Most of the sites accumulating proximal to ligatures bind the agonist carbachol with high affinity, while most of the sites accumulating distally bind carbachol with a low affinity. Also, the receptors transported in the anterograde direction are affected by a guanine nucleotide analogue (GppNHp), while those transported in the retrograde direction are less, or not, affected. The bulk of the sites along the unligated nerve trunk bind carbachol with a low affinity and are less sensitive to GppNHp modulation than the anterogradely transported sites. These results suggest that some receptors in the vagus may undergo axonal transport in association with regulatory proteins and that receptor molecules undergo changes in their binding and regulatory properties during their life cycle. These data also support the notion that the high and low affinity agonist form of the muscarinic receptor represent different modulated forms of a single receptor molecule.

Pertussis toxin-sensitive G proteins are transported toward synaptic terminals by fast axonal transport.

“…The findings in this report demonstrate that G proteins, like the other signal transduction elements, receptors, and effectors, are transported on vesicles in an anterograde direction (6-10) and, along with earlier reports of colocalized receptors and G proteins (8,27), they support the possibility that G proteins might first meet and assemble with specific receptors and effectors in an intracellular compartment within the cell body and all three elements are then transported as a complex to their site of action.…”

“…In nerve cells these signal transduction elements are found in synaptic terminals and growth cones (2)(3)(4)(5). The receptors and effectors are integral membrane proteins and, thus, are synthesized in the rough endoplasmic reticulum and then transported to terminals on vesicles by fast axonal transport (6)(7)(8)(9)(10). G protein mRNAs do not encode hydrophobic membrane-spanning segments (11), however, so it is unclear when they become associated with membranes and how they are translocated to the plasma membrane.…”

Molecular Mechanisms and Therapeutical Implications of Intramembrane Receptor/Receptor Interactions among Heptahelical Receptors with Examples from the Striatopallidal GABA Neurons

“…Subsequently, in 1981 the existence of cholecystokinin (CCK) receptor/dopamine D 2 receptor interactions using biochemical binding techniques was indicated since CCK-8 could modulate the dopamine D 2 receptor antagonist and agonist binding sites in striatal membrane preparations (Fuxe et al, 1981Agnati et al, 1983aAgnati et al, ,b, 1985. Further evidence for receptor/ receptor interactions came in 1982 from Lundberg, Bartfai, and colleagues (Lundberg et al, 1982) and from Zarbin and colleagues (Zarbin et al, 1982). Using the same type of approach, a large number of papers were published in 1983 that suggested the existence of intramembrane receptor/receptor interactions between different GPCR Agnati et al, 1984;Fuxe and Agnati, 1985).…”

Experimental localization of muscarinic receptor subtypes to cingulate cortical afferents and neurons

“…First, do lesions produce reductions in receptor density or affinity? A number of studies report that ablation and ligation techniques do not significantly alter muscarinic receptor affinity, but rather reduce receptor density (Briggs et al, 198 1;Kamiya et al, 1981;Zarbin et al, 1982;Andree et al, 1983;Mash et al, 1985). Neither is affinity affected bv dissociation nrocedures (James and Klein.…”

“…Thus, M,, or PZ-sensitive, sites may be postsynaptic on pyramidal neurons, since PZ blocks ACh-evoked depolarizations Prince, 1985, 1986). Furthermore, there is biochemical support for presynaptic localization of M, sites on cholinergic (Ganguly and Das, 1979;Nordstrom and Bartfai, 1980;Zarbin et al, 1982;Raiteri et al, 1984;Mash et al, 1985) and dopaminergic (De Belleroche et al, 1982;Raiteri et al, 1984) axons.…”