The precise signaling pathways that generate vasoconstriction following 5-HT_1B receptor stimulation have not been fully elucidated. This is illustrated in Figure 21-1, in which the most clearly established components of the signaling pathways (shown in bold) are inhibition of adenylate cyclase and opening of sarcolemmal voltage-gated L-type Ca²⁺ channels to allow Ca²⁺ influx (1,8,33,88,93, 121,122).

Following vascular 5-HT_1B receptor stimulation, the pertussis toxin (PTx)-sensitive Gi/o heterotrimer splits into Giα monomer and Gβγ dimer (66), and subsequent inhibition of adenylate cyclase and activation of Ca²⁺ influx via L-type voltage-gated Ca²⁺ channels occur concomitantly (33,121). Giα mediates adenylate cyclase inhibition (33), but the signaling pathway that links Gi/o to L-type voltage-gated Ca²⁺ channel opening is unclear, although a role for the separated Gβγ subunits has been suggested (19,42,66). The subsequent increases in intracellular free Ca²⁺ concentrations allow Ca²⁺binding to calmodulin and myosin light chain kinase (MLCK) activation. MLCK phosphorylates the 20-kDa fragment of myosin light chain, which in turn stimulates actin-myosin APTase, actin-myosin cross-bridging, and the development of force (49,118; see Fig. 1). The requirement of extracellular Ca²⁺ influx via L-type voltage-gated Ca²⁺ channels on 5-HT_1B receptor-mediated vasoconstriction is not uniform in all blood vessels that express the receptor (8,33,48,121).

A major characteristic of triptan-induced vasoconstriction is that precontraction is required in several but not all systemic blood vessels (141). In the absence of precontraction, triptan-induced contractile responses do not occur in rabbit iliac (142), mesenteric (18), renal (17), ear artery (93), or canine mesenteric artery (116), for example. However, precontraction is not required for triptan-induced vasoconstriction in human and nonhuman cerebral arteries (8,86,95,96,104,108) canine (57), and rabbit (126,130) saphenous vein, canine (26,127), and human (22,84,85)
coronary arteries. A clear explanation for these differences has not been provided thus far, although cross-talk (125) or synergy with other second-messenger responses that favor the sensitivity to (51), or availability of, intracellular free Ca²⁺ ions to the contractile proteins, such as Gq-coupled receptors, has been suggested (31).

Whether Giα-mediated inhibition of adenylate cyclase may be directly associated with vasoconstriction remains unclear (1), but amplified mitogen-activated protein kinase (MAPK) has been suggested (51) to play a role.

Calcitonin gene-related peptide (CGRP), which may be released from trigeminal sensory neurons during a migraine attack (34,35) is a potent vasodilator in systemic and cranial blood vessels (6,27,135). When CGRP activates its vascular receptors (67), the receptor complex formed (89,102) couples to the Gsα subunit, which in turn activates adenylate cyclase (52,62,67,68). CGRP-evoked increases in cyclic adenosine monophosphate (cAMP) levels activate cAMP-dependent protein kinase A isozymes (123), which cause relaxation by lowering both intracellular free Ca²⁺ concentrations and the sensitivity of the contractile elements to Ca²⁺.

Besides promoting increases in intracellular calcium concentrations, triptans may therefore be expected to partly reduce CGRP-induced vasodilatation by a postjunctional mechanism of inhibiting CGRP-activated adenylate cyclase following vascular 5-HT_1B receptor stimulation (115,136,137), in addition to the well-established prejunctional mechanism of inhibiting CGRP release from sensory afferent nerve terminals (14,77,91).

Other signaling pathways have been investigated in triptan-induced vasoconstrictor responses. The mixed phosphatidylinositol 3-kinase (PI3K) and MLCK inhibitor, wortmannin, and the MAPK inhibitor, U01296, independently inhibited 5-HT_1B-mediated contractile responses in rabbit renal artery (51), suggesting the involvement of MAPK and PI3K pathways. The MAPK pathway is generally associated with cell growth and mitogenesis (82,83), but is also suspected to be able to modulate smooth muscle contractility (87). For receptors coupled to PTx-sensitive Gi/o proteins, which include 5-HT_1B receptors, MAPK activation occurs via a PKC-independent activation of Ras (71) and Raf (107) initiated by release of βγ subunits from the heterotrimeric Gi/o proteins (23,66,70) (see Fig. 21-1). Upon activation, MAPK translocates to the nucleus where it phosphorylates transcription factors leading to subsequent mitogenesis (90). It is unknown whether phospholipase C activation is involved in 5-HT_1B receptor-mediated vasoconstriction, but a possible role for phospholipase D has been suggested (50) being dependent on the extracellular Ca²⁺ concentration and protein kinase C (50). There is no clear-cut evidence for the involvement of inositol phosphate generation associated with intracellular Ca²⁺ release in 5-HT_1B receptor-mediated vasoconstriction (see Fig. 21-1).