The functions of anterior pituitary cells are controlled by two major groups of hypothalamic and intrapituitary ligands: one exclusively acts on G protein-coupled receptors and the other activates both G protein-coupled receptors and ligand-gated receptor channels. The second group of ligands operates as neurotransmitters in neuronal cells and their receptors are termed as neurotransmitter receptors. Most information about pituitary neurotransmitter receptors was obtained from secretory studies, RT-PCR analyses of mRNA expression and immunohistochemical and biochemical analyses, all of which were performed using a mixed population of pituitary cells. However, recent electrophysiological and imaging experiments have characterized γ-aminobutyric acid-, acetylcholine-, and ATP-activated receptors and channels in single pituitary cell types, expanding this picture and revealing surprising differences in their expression between subtypes of secretory cells and between native and immortalized pituitary cells. The main focus of this review is on the electrophysiological and pharmacological properties of these receptors and their roles in calcium signaling and calcium-controlled hormone secretion.

• Keywords
• Action potentials, Calcium signaling, G protein-coupled receptors, Hormone secretion, Ligand-gated receptor channels, Neurotransmitters, Pituitary,
• MeSH
• Cell Lineage MeSH
• Pituitary Hormones, Anterior metabolism   MeSH
• Humans MeSH
• Ligands MeSH
• Receptors, Neurotransmitter metabolism   MeSH
• Signal Transduction * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Pituitary Hormones, Anterior MeSH
• Ligands MeSH
• Receptors, Neurotransmitter MeSH

Gonadotrophs are basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration. These cells fire action potentials (APs) spontaneously, coupled with voltage-gated calcium influx of insufficient amplitude to trigger gonadotropin release. The spontaneous excitability of gonadotrophs reflects the expression of voltage-gated sodium, calcium, potassium, non-selective cation-conducting, and chloride channels at their plasma membrane (PM). These cells also express the hyperpolarization-activated and cyclic nucleotide-gated cation channels at the PM, as well as GABAA, nicotinic, and purinergic P2X channels gated by γ-aminobutyric acid (GABA), acetylcholine (ACh), and ATP, respectively. Activation of these channels leads to initiation or amplification of the pacemaking activity, facilitation of calcium influx, and activation of the exocytic pathway. Gonadotrophs also express calcium-conducting channels at the endoplasmic reticulum membranes gated by inositol trisphosphate and intracellular calcium. These channels are activated potently by hypothalamic gonadotropin-releasing hormone (GnRH) and less potently by several paracrine calcium-mobilizing agonists, including pituitary adenylate cyclase-activating peptides, endothelins, ACh, vasopressin, and oxytocin. Activation of these channels causes oscillatory calcium release and a rapid gonadotropin release, accompanied with a shift from tonic firing of single APs to periodic bursting type of electrical activity, which accounts for a sustained calcium signaling and gonadotropin secretion. This review summarizes our current understanding of ion channels as signaling molecules in gonadotrophs, the role of GnRH and paracrine agonists in their gating, and the cross talk among channels.

• Keywords
• calcium signaling, electrical activity, gonadotrophs, gonadotropin-releasing hormone, ligand-gated channels, luteinizing hormone secretion, voltage-gated channels,
• Publication type
• Journal Article MeSH
• Review MeSH

Acetylcholine (ACh) has been established as a paracrine factor in the anterior pituitary gland, but the receptors mediating ACh action and the cell types bearing these receptors have not been identified. Our results showed that the expression of the nicotinic subunits mRNAs followed the order β2 > β1 = α9 > α4 in cultured rat pituitary cells. The expression of the subunits in immortalized LβT2 mouse gonadotrophs followed the order β2 > α4 = α1. M4 > M3 muscarinic receptor mRNA were also identified in pituitary and LβT2 cells. The treatment of cultured pituitary cells with GnRH down-regulated the expression of α9 and α4 mRNAs, without affecting the expression of M3 and M4 receptor mRNAs, and ACh did not alter the expression of GnRH receptor mRNA. We also performed double immunostaining to show the expression of β2-subunit and M4 receptor proteins in gonadotrophs. Functional nicotinic channels capable of generating an inward current, facilitation of electrical activity, and Ca(2+) influx were identified in single gonadotrophs and LβT2 cells. In both cell types, the M3 receptor-mediated, phospholipase C-dependent Ca(2+) mobilization activated an outward apamin-sensitive K(+) current and caused hyperpolarization. The activation of M4 receptors by ACh inhibited cAMP production and GnRH-induced LH release in a pertussis toxin-sensitive manner. We concluded that multiple cholinergic receptors are expressed in gonadotrophs and that the main secretory action of ACh is inhibitory through M4 receptor-mediated down-regulation of cAMP production. The expression of nicotinic receptors in vitro compensates for the lack of regular GnRH stimulation of gonadotrophs.

• MeSH
• Cyclic AMP metabolism   MeSH
• Electrophysiology MeSH
• Gonadotrophs MeSH
• Pituitary Gland metabolism   MeSH
• Immunohistochemistry MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Luteinizing Hormone genetics   metabolism   MeSH
• Reverse Transcriptase Polymerase Chain Reaction MeSH
• Rats, Sprague-Dawley MeSH
• Receptor, Muscarinic M3 genetics   metabolism   MeSH
• Receptor, Muscarinic M4 genetics   metabolism   MeSH
• Signal Transduction genetics   physiology   MeSH
• Calcium metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Intramural MeSH
• Names of Substances
• Cyclic AMP MeSH
• Luteinizing Hormone MeSH
• Receptor, Muscarinic M3 MeSH
• Receptor, Muscarinic M4 MeSH
• Calcium MeSH