Receptor Subtype Abundance as a Tool for Effective Intracellular Signalling

Abstract

The regulation of heart function is one of the essentials for the survival of organism. Therefore, the effective mechanisms of regulation can minimize the energy requirements and improve the ability to react to different needs on time and appropriately. Two receptor types, beta-adrenoceptors and muscarinic receptors, with almost antagonistic function, are "basic regulators" of the heart parameters. It is relevant to mention that beside the main adrenoceptors and muscarinic receptors subtypes (beta(1)- and M(2)-subtype), other minor subtypes that regulate heart function, i.e. beta-, beta-adrenoceptors, alpha(1)-adrenoceptors and minor subtypes of muscarinic receptors (M(1), M(3) and M(5)) are present in the heart. In this regard is intriguing that just two catecholamines (adrenaline, noradrenaline) have many "targets"--receptors that differ so much in the functional consequences of their activation: while beta(1)- and beta(2)-adrenoceptors cause cardiostimulation, beta(3)-adrenoceptors are responsible for cardioinhibition and alpha(1)-adrenoceptors contribute to enhanced inotropy. Similarly, some data show that other muscarinic receptors than M(2) muscarinic subtype, are expressed in the heart and these minor subtype(s) can contribute to the heart regulation in similar way as beta(3)-adrenoceptors to the catecholamine action. Taken together, regulation of heart function through different receptor subtypes and using homologous and heterologous regulation can represent an effective tool for coping with permanently changing environmental conditions.

Multitargeting nature of muscarinic orthosteric agonists and antagonists

“…Muscarinic AC-260584 (*) 7.39 (5.9) 5.0-6.16 5.23 5.0 6.0 D 2 DR 5HT 2C , 5-HT 2B AC-42 (*) 6.2 (6.2) 5.76-6.01 5.55-6.0 5.85-6.0 5.35-6.0 6.0 6.0 α 1A,B,D -AR, α 2A,B -AR, D 2 DR, D 4 DR, H 1 R, 5-HT 1A , history of use or only recently discovered), simply because they are better investigated. Another aspect that complicates the determination of appropriate receptor subtypes in specific tissues is the presence of multiple mAChR subtypes in both periphery tissues, e.g., the retina (Ruan et al, 2021) and heart (Myslivecek et al, 2008a;Myslivecek et al, 2008b), and CNS tissues, e.g., the striatum (Felder et al, 2018), hippocampus (Ohno-Shosaku et al, 2003) and other tissues. In the CNS, the presence of multiple mAChR subtypes on the same structure (presynaptic or postsynaptic) thus complicates the identification of target structures.…”

“…Additionally, very well-established ligands (with a long history of use in MR research, e.g., atropine) are expected to exhibit more additional targets than less established ligands (with a short history of use or only recently discovered), simply because they are better investigated. Another aspect that complicates the determination of appropriate receptor subtypes in specific tissues is the presence of multiple mAChR subtypes in both periphery tissues, e.g., the retina ( Ruan et al, 2021 ) and heart ( Myslivecek et al, 2008a ; Myslivecek et al, 2008b ), and CNS tissues, e.g., the striatum ( Felder et al, 2018 ), hippocampus ( Ohno-Shosaku et al, 2003 ) and other tissues. In the CNS, the presence of multiple mAChR subtypes on the same structure (presynaptic or postsynaptic) thus complicates the identification of target structures.…”

Elements toward novel therapeutic targeting of the adrenergic system

“…For instance, whereas a1-ARs act via protein kinase C (PKC) activation with both phospholipase C (PLC) (de Smet et al, 2011) and inositol 1,4,5-triphosphate (IP3) as second messengers (Lafontan and Berlan, 1993;Myslivecek et al, 2008), a 2-ARs reduce intracellular cyclic adenosine monophosphate (cAMP) through adenylyl cyclase (Ac) activation (Myslivecek et al, 2008). Both a-AR and β-AR subtypes have been shown to be expressed on mammalian innate immune cells (Nance and Sanders, 2007).…”