G PROTEIN SIGNALLING MEDIATES NEUROTRANSMITTER ACTION: EMPHASIS ON NEUROTENSIN

M. Felaco¹ and P. Felaco^2*

¹ Department of Medicine and Science of Aging, University “G. D’Annunzio”, Chieti, Italy;
² UOC Nephrology and Dialysis PO, Teramo, Italy.

*Correspondence to:
Paolo Felaco,
UOC Nephrology and Dialysis PO,
64100 Teramo, Italy.
e-mail: pfelaco@gmail.com

Received: 28 April, 2026 Accepted: 30 June, 2026

ISSN 2279-5855 print / 3103-7364 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Neurotransmitters bind to G protein-coupled receptors (GPCRs) to activate G proteins, generate intracellular second messengers, and produce functional changes in neurons. G-protein-mediated signalling is a transduction mechanism through which neurotransmitters exert their effects in the nervous system. GPCRs translate neuropeptide binding into intracellular responses that regulate neuronal excitability, synaptic transmission, and gene expression. Neurotensin is a neurotransmitter that is widely distributed in the central nervous system (CNS) which has the ability to modulate numerous neurochemical pathways, particularly dopaminergic ones. Through the activation of its predominant GPCRs (NTSR1 and NTSR2), neurotensin induces the activation of multiple intracellular signalling pathways involved in the regulation of pain, thermoregulation, food intake, neuroendocrine functions, and cognitive processes. This article reviews the fundamental principles of G-protein-mediated signalling and explores the role of neurotensin as a model peptide neurotransmitter, highlighting its molecular mechanisms and physiological and pathological implications. Understanding the interactions between neurotensin, GPCRs, and intracellular signalling pathways may contribute to the development of new therapeutic strategies for CNS disorders.

KEYWORDS: G protein, signalling, GPCR, neuropeptide, neurotensin

INTRODUCTION

G proteins are molecular switches that translate signals from receptors to cells (1). The G protein is composed of three proteins: Gα (45 kDa), Gβ (35 kDa), and Gγ (8 kDa) (2).  Many neurotransmitters exert their effects on nerve cells through G protein-mediated signalling (3,4). This binding causes a conformational change and activates the associated G proteins intracellularly. G proteins transduce the signal to specific intracellular effectors (Fig.1).

Fig. 1. G protein activation occurs when the Gα subunit replaces GDP with GTP. This dissociates the protein into Gα-GTP and the Gβγ complex, both of which act as intracellular effectors. The two components activate various target proteins and signalling pathways, contributing to the cellular response.

G proteins activate or inhibit the adenylate cyclase pathway and enzymes that produce second messengers, as well as stimulating the production of ATP, which is converted to cAMP (5). Increased cAMP activates protein kinase A (PKA), while the Gi protein has the opposite effect, inhibiting adenylate cyclase and reducing cAMP in the phospholipase C (PLC) pathway (6).

Neurotensin is a neuropeptide that acts as a neurotransmitter and neuromodulator in the central and peripheral nervous systems with effects that are mediated primarily by GPCRs (NTSR1, and NTSR2) (7).

G PROTEIN MEDIATED SIGNALLING

Neurotransmitters are known to generate information in neurons through G-protein-mediated signalling. Compared to ionotropic receptors, GPCRs activate a slower but highly versatile intracellular cascade. The G protein is associated with the cytoplasmic membrane (8). The neurotransmitter acts as a ligand that binds to the GPCR receptor on the target cell membrane. Neurotransmitters that utilize the GPCR include norepinephrine, serotonin, dopamine, acetylcholine, GABA, and glutamate (9).

The α subunit binds guanosine diphosphate (GDP), while the α, β, and γ subunits form an inactive complex. The α-GDP plus the βγ receptor, composed of a G protein, is inactive, and when the neurotransmitter binds to the GPCR, it activates and changes conformation (10). The α subunit releases GDP, while α-GDP binds and becomes α-guanosine triphosphate (GTP). At this point, the G protein cleaves into α-GTP and a βγ complex (11). These proteins are capable of activating intracellular targets. The main signal transduction pathway is the Gs (stimulatory) pathway. The α subunit activates adenylate cyclase, which converts ATP to cAMP. cAMP activates protein kinase A (PKA), transcription factors, and ion channels. These reactions lead to increased neuronal excitability, changes in gene expression, and synaptic plasticity (12).

In the inhibitory Gi pathway, the αi subunit inhibits adenylate cyclase, reducing cAMP production. The βγ complex opens K⁺ channels and closes Ca²⁺ channels (13). Hyperpolarization leads to a decrease in neurotransmitter release. In the Gq pathway, the αq subunit activates phospholipase C (PLC), which cleaves the membrane phospholipid PIP₂, leading to the formation of inositol triphosphate (IP3) plus diacylglycerol (DAG), which diffuses into the cytoplasm and opens Ca^2⁺ channels in the endoplasmic reticulum. This leads to an increase in intracellular calcium and the presence of DAG in the membrane, activating protein kinase C (PKC). These effects cause secretion, contraction, and changes in synaptic transmission (14) (Fig.2).

Fig. 2. Neurotensin activates its receptor, NTSR1, inducing a cascade of activation that leads to the small GTPase RhoA through intracellular signalling pathways. RhoA activation promotes cytoskeletal reorganization, regulating cell shape, motility, and adhesion.

Activation of GPCRs can modulate ion channels, the opening and closing of K⁺ channels, and the modulation of Ca²⁺ channels. Presynaptic receptors can reduce or increase synaptic vesicle release and modify gene expression through PKA, PKC, and MAPK (15).

The α subunit possesses GTPase activity (α-GTP leads to the formation of α-GDP plus Pi), and the G protein becomes inactive. Receptor desensitization occurs when the GPCR is phosphorylated by GPCR kinase and binds to β-arrestin, causing uncoupling from the G protein, receptor internalization, and a reduced cellular response (16). Several neurotransmitters, such as dopamine, serotonin, norepinephrine, muscarinic acetylcholine, and GABA, exert their biological effects by binding to membrane receptors called GPCRs (17). This binding causes a conformational change and activates an associated G protein intracellularly. In turn, the G protein transduces the signal to specific intracellular effectors.

G protein-mediated transmission is slower (hundreds of milliseconds or seconds), longer-lasting, and more amplifiable than ionotropic receptors, allowing for changes in the entire functional state of the neuron (18). These biological effects are critical for learning and memory, motor control, pain modulation, attention, and mood regulation (19).

NEUROTENSIN AND G-PROTEIN-COUPLED RECEPTORS

Neurotensin is a 13-amino acid neuropeptide present in the central nervous system (CNS) and gastrointestinal tract (unlike many classic neurotransmitters, which are much smaller molecules) first isolated by Susan Leeman that acts primarily through GPCR receptors NTSR1 and NTSR2 (20,21). It acts both as a neurotransmitter and as a local hormone. When neurotensin binds to the NTSR1 receptor (GPCR), several intracellular pathways are activated, leading to an increase in intracellular Ca²⁺, activation of PKC, phosphorylation of numerous cellular proteins, and altered ion channel activity (22). By activating MAPK (ERK), neurotensin can activate the ERK/MAPK signalling pathways, which regulate cell differentiation, growth, neuronal plasticity, and gene expression (23).

The effects of neurotensin are mediated primarily by GPCRs (24).  The main neurotensin receptors, NTSR1 and NTSR2, both belong to the GPCR family. Neurotensin binds to the NTSR1 receptor on the cell membrane, causing a conformational change in the receptor and the activation of an intracellular G protein. The associated G protein is predominantly of the Gq/11 type (25). The α subunit replaces GDP with GTP and separates from the βγ complex. The αq-GTP subunit activates PLC, which cleaves the phospholipid PIP₂ into IP3 and DAG. These reactions continue as previously described for the activation of other neurotransmitters (26).

Neurotensin is particularly important because it interacts with the dopaminergic system in brain areas such as the ventral tegmental region, the nucleus accumbens, and the stratum corneum. Neurotensin can modulate the activity of dopaminergic neurons, influencing reward, feeding behavior, motivation, and motor control-the classic neurotensin pathway. In some cells, the NTSR1 receptor can also activate other signalling pathways (MAPK/ERK, β-arrestin, and other intracellular cascades), further expanding its biological effects.

Neurotensin plays a pathological role in obesity, Parkinson’s disease, drug addiction, and schizophrenia (27). Indeed, neurotensin receptors are being studied as potential drug targets. Neurotensin differs from classical neurotransmitters both in its chemical nature and in the way it is synthesized, released, and acts on target cells (28). The difference between neurotensin and other neurotransmitters is that classic neurotransmitters are synthesized directly in the nerve terminal by local enzymes, while neurotensin is produced as a large precursor protein (pro-neurotensin) in the neuron’s cell body and is subsequently cleaved into active peptides. Furthermore, classic neurotransmitters are contained in small, transparent synaptic vesicles, while neurotensin is stored in large, dense vesicles (dense-core vesicles), often along with other neurotransmitters (29). A neuron can simultaneously release both dopamine plus neurotensin and glutamate plus neurotensin. Furthermore, classic neurotransmitters are readily released even at low neuronal firing rates, while neurotensin requires high-frequency firing, intense stimulation, and greater increases in intracellular Ca²⁺. In fact, neurotensin acts especially when the neuron is highly active (30).

Many classic neurotransmitters have both ionotropic (fast) and metabotropic (slow) receptors. Neurotensin acts almost exclusively through metabotropic GPCRs (NTSR1 and NTSR2). Classic neurotransmitters transmit specific information such as excitation, inhibition, and rapid communication, while neurotensin acts primarily as a neuromodulator, modifying the dopamine response, regulating satiety, influencing pain, and modifying synaptic plasticity (31).

CONCLUSIONS

Neurotransmitters bind to a GPCR to activate a G protein, generate intracellular second messengers (cAMP, IP₃, DAG, Ca²⁺), and produce changes in excitability, neurotransmitter release, and gene expression of the target cell. G-protein signalling is one of the most important mechanisms through which neurotransmitters modulate neuronal activity, influence cellular excitability, and mediate synaptic transmission and gene expression. The neurotransmitter neurotensin is crucial for the activation of its GPCR. Neurotensin modulates numerous neuroendocrine circuits involved in dopamine control, pain perception, mood regulation, and other processes. Neurotensin is a prominent example of how G-protein-mediated signal transduction translates an extracellular signal into complex cellular responses.

Conflict of interest

The authors declare that they have no conflict of interest.

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