The striatum and cerebral cortex express different muscarinic receptor mRNAs

Abstract

The existence of four distinct muscarinic acetylcholine receptor genes (ml -m4) has recently been demonstrated. cDNAs for three of these receptors have been cloned from brain (ml, m3, m4) and one from heart (m2). To gain some understanding of the physiological role of the brain muscarinic receptors, we mapped the distribution of their mRNAs in rat brain by in situ hybridization.These mRNAs are barely detectable in the hindbrain and cerebellum. Within forebrain, each mRNA has a strikingly different pattern of distribution.The highest levels of ml mRNA are in the cerebral cortex and hippocampus followed by the striatum. m3 mRNA is also prominent in the cerebral cortex, but has very low levels in the striatum. Conversely, the levels of m4 mRNA are highest in the striatum. Since the cognitive effects of muscarinic drugs have been localized to the cerebral cortex and hippocampus, and their psychomotor effects to the striatum, these data suggest that the muscarinic receptors which subserve these responses may be different gene products. Finally, we show that these muscarinic receptors can be distinguished pharmacologically, suggesting that it may be possible to develop drugs for the selective treatment of the psychomotor vs cognitive difficulties of Parkinson's and Alzheimer's disease, respectively.

Tissue distribution of mRNAs encoding muscarinic acetylcholine receptor subtypes

“…It has previously been reported that rat pancreas contains mAChR III mRNA, but not mAChR I mRNA [6]. The presence of all four mAChR mRNAs in cerebrum agrees with previous observations as does the presence of mAChR II mRNA in heart [2,3,5,6,24]. The differential tissue distribution of the four mAChR mRNAs observed in the present investigation strengthens our previous conclusion that the mAChR heterogeneity in tissues with respect to antagonist binding is attributable to the presence of individual moIecuIarly distinct mAChR subtypes or various combinations of them [8].…”

The distribution of a dopamine D2 receptor mRNA in rat brain

“…The widespread distribution of this mRNA has important implications with regard to the pharmacology of dopamine receptors and future prospects for the development of dopaminergic drugs which discriminate between receptors located in these different brain regions. In the case of other G-protein coupled receptors, it has been shown that when the same receptor genes are expressed in different cells, their antagonist pharmacology does not vary with respect to cell type [25,26,36], while agonist pharmacology varies with respect to both cell type and levels of receptor ( [28] and unpublished observations). Initial results with the cloned D2 receptors indicate that a similar relationship may hold since D2 receptors expressed in fibroblasts have the same affinity for antagonists and a lower affinity for agonists than do D2 receptors expressed by brain [30].…”

“…For example, several subtypes of muscarinic, serotonergic, and adrenergic receptors have now been cloned [19][20][21][22][23][24][25][26]. These receptor subtypes are expressed in distinct regions of the brain, and in the case of muscarinic receptors, different receptor gene products are expressed in presynaptic versus postsynaptic locations [27][28][29]. Recently, a cDNA sequence for a rat brain D2 receptor was reported showing significant sequence homology with receptors that mediate signal transduction by coupling with G-proteins [30].…”

Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

“…Recent findings suggest that the muscarinic receptors in rat striatum (McKinney et al 1989;Waelbroeck et al 1990) and NG1 08-15 cells Baumgold and White 1989) are pharmacological equivalents (M 4 receptors) of the m4 gene (Brann et al 1988;Peralta et al 1987). In Fig.…”