Function and Role of Histamine H1 Receptor in the Mammalian Heart

Abstract

Histamine can change the force of cardiac contraction and alter the beating rate in mammals, including humans. However, striking species and regional differences have been observed. Depending on the species and the cardiac region (atrium versus ventricle) studied, the contractile, chronotropic, dromotropic, and bathmotropic effects of histamine vary. Histamine is present and is produced in the mammalian heart. Thus, histamine may exert autocrine or paracrine effects in the mammalian heart. Histamine uses at least four heptahelical receptors: H₁, H₂, H₃ and H₄. Depending on the species and region studied, cardiomyocytes express only histamine H₁ or only histamine H₂ receptors or both. These receptors are not necessarily functional concerning contractility. We have considerable knowledge of the cardiac expression and function of histamine H₂ receptors. In contrast, we have a poor understanding of the cardiac role of the histamine H₁ receptor. Therefore, we address the structure, signal transduction, and expressional regulation of the histamine H₁ receptor with an eye on its cardiac role. We point out signal transduction and the role of the histamine H₁ receptor in various animal species. This review aims to identify gaps in our knowledge of cardiac histamine H₁ receptors. We highlight where the published research shows disagreements and requires a new approach. Moreover, we show that diseases alter the expression and functional effects of histamine H₁ receptors in the heart. We found that antidepressive drugs and neuroleptic drugs might act as antagonists of cardiac histamine H₁ receptors, and believe that histamine H₁ receptors in the heart might be attractive targets for drug therapy. The authors believe that a better understanding of the role of histamine H₁ receptors in the human heart might be clinically relevant for improving drug therapy.

Keywords: histamine; histamine H1 receptor; human heart; signal transduction.

Figure 1

Proven signal transduction pathways for the histamine H₁ receptor in principle. Histamine H₁ receptors convey their effects primarily via GTP binding proteins. This leads to stimulation of PLC activity. Histamine H₁ receptors can activate also phospholipase A2 (PLA2), leading to the formation of arachidonic acid (AA). After that, inositoltrisphosphate (IP₃) and diacylglycerol (DAG) are formed. DAG activates protein kinase C (PKC). PKC then phosphorylates target proteins and starts a cascade with other kinases called MEK and ERK. IP₃ acts on IP₃ receptors. [34]. Ca²⁺ activates Ca²⁺-dependent proteins; e.g., Ca²⁺ calmodulin-dependent protein kinase II (CamKII) and the stimulation of adenylyl cyclases. cAMP-dependent protein kinase (PKA) can phosphorylate phospholamban (PLB), the ryanodine receptor (RYR), the L-type Ca²⁺-channel (LTCC), the transcription factor CREB, and the inhibitory subunits of troponin (TnI). In the SR, Ca²⁺ binds to calsequestrin (CSQ) and exits the SR via RYR. Ca²⁺ can activate nitric oxide (NO) synthases (NOS), stimulate guanylyl cyclases (GC). cGMP can activate or inhibit phosphodiesterases (PDEs. Histamine H₁ receptors might also activate tyrosine kinases (Y-kinase. Histamine H₁ receptors can inhibit (I_Kr) or activate (I_Ks) potassium channels (K) in the sarcolemma. Histamine H₁ receptors can induce early response genes, but also via altered gene transcription (via MAPK and NFkappaB).