The Cardiovascular Actions of DOPA Mediated by the Gene Product of ocular albinism 1

Abstract

Abstract. l-3,4-Dihydroxyphenylalanine (DOPA) is the metabolic precursor of dopamine, and the single most effective agent in the treatment of Parkinson's disease. One problem with DOPA therapy for Parkinson's disease is its cardiovascular side effects including hypotension and syncope, the underlying mechanisms of which are largely unknown. We proposed that DOPA is a neurotransmitter in the central nervous system, but specific receptors for DOPA had not been identified. Recently, the gene product of ocular albinism 1 (OA1) was shown to possess DOPAbinding activity. It was unknown, however, whether or not OA1 is responsible for the actions of DOPA itself. Immunohistochemical examination revealed that OA1 was expressed in the nucleus tractus solitarii (NTS). OA1-positive cells adjacent to tyrosine hydroxylase-positive cell bodies and nerve fibers were detected in the depressor sites of the NTS. OA1 knockdown using oa1-specific shRNA-adenovirus vectors in the NTS reduced the expression levels of OA1 in the NTS. The prior injection of the shRNA against OA1 suppressed the depressor and bradycardic responses to DOPA but not to glutamate in the NTS of anesthetized rats. Thus OA-1 is a functional receptor of DOPA in the NTS, which warrants reexamination of the mechanisms for the therapeutic and untoward actions of DOPA.

GPCR signalling from within the cell

“…Emerging studies, however, indicate that certain intracellular membranes may serve as alternate destinations or even the preferred location for a number of GPCRs where they may couple to different signalling systems and exhibit distinct patterns of subcellular distribution (Irannejad et al ., , ; Jong et al ., ; Branco and Allen, ; Calebiro et al ., ; Campden et al ., ; Joyal et al ., ). One example of an exclusively intracellular GPCR is that of the ocular albinism I (OA1) GPCR, GPR143 (Goshima et al ., ; De Filippo et al ., ). GPR143 localize to melanosomes and late endosomes/lysosomes in pigmented and non‐pigmented cells, where they appear to act as ‘sensors’ regulating organelle biogenesis and maturation (Schiaffino et al ., ; d'Addio et al ., ; Samaraweera et al ., ).…”

Intracellular GPCRs Play Key Roles in Synaptic Plasticity

“…Certain intracellular membranes may even serve as alternate destinations or even the preferred location for a number of GPCRs where they may couple to different signaling systems and exhibit distinct patterns of subcellular distribution (3–8). Some of the first examples of intracellular GPCRs include the ocular albinism I (OA1) GPCR, or GPR143 (9, 10) which localizes to melanosomes and late endosomes/lysosomes in pigmented and non-pigmented cells (11); the prostaglandin EP 3 and EP 4 receptors which signal from nuclei in many tissues including the brain (12), and mGlu 5 receptors which also signals from neuronal nuclei as well as from ER membranes (13). In addition, GPCRs have been found on vesicles, mitochondria (14), outer and inner nuclear membranes (3, 8, 15, 16), and even within the nucleoplasm on nuclear bodies and/or nuclear invaginations (17–19).…”

The Many Faces of G Protein-Coupled Receptor 143, an Atypical Intracellular Receptor

“…Goshima and co-workers, who performed microinjections into the nucleus tractus solitarius (NTS) to investigate cardiovascular actions of L-DOPA through GPR143, could not exclude that dopamine converted from L-DOPA in non-neuronal tissues would be also able to exert cardiovascular and/or renal actions through β-adrenergic receptor and dopamine receptors D 1 R and D 2 R ( Goshima et al, 2014 ). It was shown that D 1 R activity in vascular smooth muscle is associated with vasodilatation ( Kohli, 1990 ).…”